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)

Thiamine-deficient encephalopathy is characterized by morphologic lesions in the brainstem and less extensively in the cerebellum, but the early neurologic signs reverse rapidly and fully with thiamine, indicating a metabolic disorder. The suggested causal mechanisms of the encephalopathy involve two thiamine-dependent enzymes: (a) impairment of pyruvate decarboxylase activity with decreased cerebral energy (ATP) synthesis, and (b) reduction of transketolase activity with possible impairment of the hexose monophosphate shunt and subsequent decrease in NADPH formation. The latter may be important in maintaining glutathione in a reduced form (GSH), which apparently functions by keeping enzymes in a reduced (active) conformation. To examine some of these postulated mechanisms, in this study we measured pyruvate decarboxylase and transketolase activity, lactate, ATP and GSH levels in the cerebral cortex, cerebellum, and brainstem, and thiamine concentration in whole brain of rats with diet-induced low thiamine encephalopathy. Pair-fed and normally fed asymptomatic control animals were similarly investigated. To assess the functional importance of some of our results, we repeated the studies in rats, immediately (16-36 hr) after reversal of the neurological signs with thiamine administration. THE DATA OBTAINED LED TO THE FOLLOWING CONCLUSIONS: (a) Brain contains a substantial reserve of thiamine in that thiamine level has to fall to below 20% of normal before the onset of overt encephalopathy and an increase in brain thiamine to only 26% of normal results in rapid reversal of neurologic signs. (b) Both cerebral transketolase and pyruvate decarboxylase activities are impaired in low thiamine encephalopathy and the abnormality in the pyruvate decarboxylase is reflected in a rise in brain lactate. These biochemical abnormalities occur primarily in the brainstem and cerebellum, the sites of the morphologic changes. (c) Although the fall in cerebral transketolase is about twofold greater than that of pyruvate decarboxylase activity during encephalopathy, both enzymes rise on reversal of neurologic signs and the degree of the transketolase rise is slight. Accordingly, this study cannot ascertain the relative functional importance of these two pathways in the induction of the encephalopathy. The data suggest, however, that the depression of transketolase is not functionally important per se, but may only be an index of some other critical aspect of the hexose monophosphate shunt. (d) The normal cerebral ATP concentration and small GSH fall during encephalopathy, with little GSH rise on reversal of neurologic signs, suggest that a depletion of neither substance is instrumental in inducing thiamine-deficient encephalopathy.
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PMID:Encephalopathy of thiamine deficieny: studies of intracerebral mechanisms. 567 22

Formation of excited species such as singlet molecular oxygen during redox cycling (one-electron reduction-oxidation) was detected by low-level chemiluminescence emitted from perfused rat liver and isolated hepatocytes supplemented with the quinone, menadione (vitamin K3). Chemiluminescence was augmented when the two-electron reduction of the quinone catalyzed by NAD(P)H:quinone reductase was inhibited by dicoumarol, thus underlining the protective function of this enzyme also known as DT-diaphorase. Interference with NADPH supply by inhibition of energy-linked transhydrogenase by rhein or of mitochondrial electron transfer by antimycin A led to a depression in the level of photoemission. Unexpectedly, glutathione depletion of the liver led to a lowering of chemiluminescence elicited by menadione, whereas conversely the depletion of glutathione led to increased chemiluminescence levels when a hydroperoxide was added instead of the quinone. As the GSH conjugate of menadione, 2-methyl-3-glutathionyl-1,4-naphthoquinone, studied with microsomes, was shown also to be capable of redox cycling, we conclude that menadione-induced chemiluminescence of the perfused rat liver does not only arise from menadione itself but from the menadione-GSH conjugate as well. Therefore, the conjugation of the quinone with glutathione is not in itself of protective nature and does not abolish semiquinone formation. A biologically useful aspect of conjugate formation resides in the facilitation of biliary elimination from the liver. Nonenzymatic formation of the conjugate from menadione and GSH in vitro was found to be accompanied by the formation of aggressive oxygen species.
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PMID:Hepatic low-level chemiluminescence during redox cycling of menadione and the menadione-glutathione conjugate: relation to glutathione and NAD(P)H:quinone reductase (DT-diaphorase) activity. 619 66

The effects of dithiocarb and (+)-catechin on the microsomal mixed-function oxidase system of rat liver were investigated after a single dose as well as after repeated treatment for 7 and for 28 days. Dithiocarb (200 mg/kg p.o.) significantly reduced the microsomal cytochrome P-450 content, aniline hydroxylase and aminopyrine demethylase activities; maximum decrease was observed at 4 hrs, return to normal values after 24 hrs. (+)-catechin (200 mg/kg p.o.) had no effects in this respect. Both agents did not affect microsomal enzyme activities when applied orally for 7 days. After 28 days treatment only dithiocarb (50 - 100 - 200 mg/kg p.o.) exerted a dose-dependent depression of the aniline hydroxylase activity. In vitro experiments confirmed the in vivo observations: a concentration-dependent inhibition of the aniline hydroxylation and aminopyrine demethylation were seen from the addition of dithiocarb, the I50-values were 5.4 X 10(-6) M and 9.6 X 10(-5) M, respectively. (+)-catechin showed no inhibitory activity on both enzyme activities in vitro. Both dithiocarb and (+)-catechin depressed the activity of the NADPH-cytochrome C-reductase only in the 10(-4) M concentration range, these effects should be therefore evaluated as non-physiological without relevance in vivo.
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PMID:Effects of dithiocarb and (+)-catechin on microsomal enzyme activities of rat liver. 628 65

Interferon inducers, poly I:poly C, endotoxin, hepatic RNA, and Tilorone, were administered to rats at different time points in relation to the onset of hyperoxic exposure (O2 greater than 97%). All interferon inducers tested significantly reduced the mortality of rats when compared with the control groups. In hyperoxia alone, malondialdehyde, a product of lipid peroxidation, was significantly increased and the microsomal enzyme NADPH cytochrome c reductase decreased as measured in the whole lung. With the administration of either endotoxin or poly I:poly C these two parameters remained within the range of control values. These data suggest that the administration of interferon inducers protects against hyperoxic microsomal damage. After the administration of these interferon inducers with or without hyperoxia the increased activity of heme oxygenase and marked reduction of the heme content of microsomes were demonstrated. Since cytochrome P-450 and b5 are the major hemoproteins of microsomes and the known source of oxygen-free radical generation, the results obtained in this study appear to indicate that the depression of the hemoprotein of microsomes by the administration of interferon inducers may be largely responsible for the protective effects of these agents against hyperoxia.
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PMID:Protective effect of interferon inducers against hyperoxic pulmonary damage. 654 2

Three experiments were carried out to determine the effects of feeding a niacin-free diet (NFD) to immature quail. The first two experiments demonstrated that the results were influenced by the age of the birds. Birds placed on test at 4 weeks of age (57 g) had reduced growth rates but did not readily develop niacin deficiency symptoms. In contrast, newly hatched chicks (7.2 g) were highly sensitive as all birds died within 9 days of being fed the NFD. In the third experiment the NFD was fed to birds that were intermediate in weight (19 g) to those in the first two experiments. Niacin deficiency led to a marked depression in growth, closure of eyes, reduced activity and a marked atrophy of the pectoral muscle. There was a dramatic reduction in the level of NAD and NADPH in the pectoral muscle but not in other tissues. The niacin status of quail did not affect the activity levels of metabolically related or unrelated enzymes in liver or pectoral muscle. It may be concluded that niacin deficiency reduces pyridine nucleotide levels in muscle tissue but not other tissues and that it does not affect the activity level of certain enzymes in muscle or liver tissue.
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PMID:Effects of niacin deficiency on pyridine nucleotide levels and enzyme activities in various organs of young growing quail. 707 17

The primary defence mechanism of myocytes against peroxides and peroxide-derived peroxyl and alkoxyl radicals is the glutathione redox cycle. The purpose of the present study was to increase the turnover rate of this cycle by stimulating the glutathione peroxidase catalysed reaction (2GSH-->GSSG), the glutathione reductase catalysed reaction (GSSG-->2GSH), or both. Neonatal rat heart cell cultures were subjected to a standardized protocol of oxidative stress using 80 mumol.l-1 cumene hydroperoxide (CHPO) for 0-90 min. The consequences of this protocol were described in terms of cellular concentrations of GSH, GSSG, NADPH and ATP, formation of malondialdehyde (MDA), release of GSSG and of ATP catabolites, depression of contraction frequency, cellular calcium overload, and enzyme release. Trolox-C, an analogue of vitamin E, accelerated the glutathione peroxidase reaction leading to lowering of GSH concentration and the GSH/GSSG ratio, less MDA formation, diminished negative chronotropy, delayed calcium overload, and less enzyme release. Glucose was used to accelerate the glutathione reductase reaction by supplying NADPH, leading to higher GSH concentration and a higher GSH/GSSG ratio, less MDA formation, diminished negative chronotropy, unchanged development of calcium overload, and less enzyme release. As a full turn of the glutathione redox cycle involves both the peroxidase and the reductase reactions, the combination of Trolox-C and glucose was superior to either of the two alone: 90 min following addition of CHPO together with Trolox-C and glucose, the GSH concentration and the GSH/GSSG ratio were almost normal, MDA formation was extremely low, calcium overload was markedly delayed, and enzyme release hardly occurred at all. Cells remained beating in the observation period of 30 min. We conclude that the capacity of the glutathione redox cycle to withstand oxidative stress can be increased by stimulation of either the peroxidase reaction or the reductase reaction, and that optimal redox cycling is achieved by stimulation of both reactions.
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PMID:Protection of myocytes against free radical-induced damage by accelerated turnover of the glutathione redox cycle. 767 3

Toxicosis due to paraquat, a redox cycling xenobiotic, is still a subject of much debate. In the present study on lipid peroxidation, paraquat had a biphasic effect on the malondialdehyde (MDA) level in rat liver microsomes; stimulation at the initial stage (within 10 min) and depression at the later stage. Although paraquat increased the initial rate of NADPH oxidation dose-dependently, the rate was not necessarily parallel with the increase in the MDA level. The MDA level increased linearly up to 0.1 mM paraquat added, but then it attained a plateau. The stimulation obtained by paraquat within 10 min was absolutely dependent on exogenous Fe2+ ion and NADPH, and the stimulation was entirely SOD sensitive, while the iron-driven increase in MDA was 20% sensitive. Thus, there were different mechanisms between iron-driven lipid peroxidation and paraquat-modified peroxidation. Catalase increased the level, but mannitol, a scavenger of OH, had no effect. EPR spectra showed that superoxide was formed dose-dependently up to 0.1 mM paraquat and that it attained a plateau at the same as MDA level described above. From these results, we concluded that paraquat stimulates lipid peroxidation through a mechanism dependent on the superoxide complex involving Fe2+ ion.
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PMID:Effect of paraquat on the malondialdehyde level in rat liver microsomes (in vitro). 802 66

Anthraquinone dyes are utilized by the military in colored-smoke grenades. During production, workers in munitions plants may be exposed to fugitive emissions of these dyes or mixtures thereof. The effects of a prototype violet dye mixture (VDM) consisting of Disperse Red 11 (DR11), [1,4-diamino-2-methoxy-anthraquinone] and Disperse Blue 3 (DB3) [1-methylamino-4-hydroxyethylamino-anthraquinone] on F344 male and female rats have been investigated. Acute 1-day inhalation exposures (6 hr) to VDM were conducted at 1000, 300, 100, 70, 40, and 10 mg/m3, with an additional exposure to 40 mg/m3 6 hr/day for 5 days; 4.22 +/- 2.1 microns (MMAD +/- delta g). Lung burdens of dye, general histopathology, and/or liver function were evaluated at 0, 3, and 7 days postexposure. Unexpected lethality due to severe liver damage was observed with acute exposures of > or = 300 mg/m3 and in the 5-day 40 mg/m3 exposures. Centrilobular degeneration and necrosis of liver cells was concentration-dependent with inhalation of VDM > or = 40 mg/m3. In addition, nasal olfactory epithelium exhibited degeneration and necrosis with acute exposures > or = 10 mg/m3. Lung instillations at 250, 500, and 1000 micrograms of the VDM revealed no lung or liver toxicity. Because per os exposure due to preening was suspected as a major exposure route, a gavage study with the VDM and its two component dyes DR11 and DB3 (800 mg/kg) was undertaken. One day following gavage with DR11 or DB3, serum enzymes indicative of liver toxicity (LDH, SGPT, SDH, and ICDH) were slightly elevated (1-6x control). However, rats gavaged with VDM had serum enzyme levels 10-100x control by Day 1 after gavage, indicating acute liver toxicity. Activities of liver enzymes involved in xenobiotic and glutathione metabolism were also acutely affected. All of the dyes caused various degrees of induction of glucose-6-phosphate dehydrogenase, glutathione reductase, glutathione peroxidase, and nonprotein sulfhydryls. The enzymes involved in xenobiotic metabolism (glutathione S-transferase, NADPH cytochrome-c reductase, and P450) were also elevated by the two component dyes, in contrast to their significant depression with VDM treatment. The similarity between the liver and olfactory epithelium effects of these compounds and the lack of pulmonary tissue effects is not fully understood, but the interaction of the individual dyes as VDM emphasizes the need to assess chemicals such as the anthraquinones as their likely-to-be-encountered mixtures.
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PMID:Toxicity of an anthraquinone violet dye mixture following inhalation exposure, intratracheal instillation, or gavage. 812 3

The present study examined the hypothesis that cholinergic neurons in the pedunculopontine tegmental nucleus (PPT) can cause the release of acetylcholine (ACh) in the pontine reticular formation and contribute to respiratory depression. In vivo microdialysis of the gigantocellular tegmental field (FTG) was performed in 10 adult male cats while respiration was being measured. In four intact, unanesthetized cats these measurements were obtained during states of quiet wakefulness and during the rapid eye movement (REM) sleeplike state caused by FTG microinjections of carbachol. The results demonstrate a simultaneous time course of enhanced ACh release in the FTG and respiratory rate depression. In six barbiturate-anesthetized cats similar measurements were obtained while PPT regions containing NADPH-positive neurons were electrically stimulated. PPT stimulation caused increased ACh release in the FTG and caused respiratory rate depression. Together, these findings are consistent with the hypothesis of a causal relationship between ACh release in the FTG and respiratory depression.
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PMID:Pedunculopontine stimulation alters respiration and increases ACh release in the pontine reticular formation. 845 6

The role of the polymorphonuclear neutrophil (PMN) on MOF is analyzed either as PMN activation for superoxide and enzyme release, or as PMN function depression after trauma and surgery. The authors stress: 1) the signal transduction pathway from the PMN membrane receptors to the effector response; 2) the PMN-NADPH system structure and function; 3) the functional states of the PMN (quiescente, primed, activated, non-responsive) in terms of the NADPH system activation; 4) the mechanism of tissue injuiry by the PMN. Clinical investigations on the PMN activation state, and therapeutical goals based on recent clinical investigations are also discussed.
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PMID:[The role of the polymorphonuclear neutrophil in the failure of multiple organs and systems]. 876 51


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