Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.3.3.1 (citrate synthase)
4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In substantia nigra from patients with Parkinson's disease, there are decreased levels of reduced glutathione (GSH) and diminished activities of mitochondrial complex I and alpha-ketoglutarate dehydrogenase (alpha-KGDH), along with increased activity of superoxide dismutase (SOD). However, the interrelationship among these events is uncertain. We now report the effect of decreased brain GSH levels on SOD and mitochondrial respiratory enzyme activity in rat brain. In addition, we have investigated the ability of thioctic acid, an endogenous antioxidant, to alter these parameters. Unilateral or bilateral intracerebroventricular (ICV) administration of buthionine sulphoximine (BSO; 1 x 3.2 mg or 2 x 1.6 mg) over a 48-hr period reduced cortical GSH by 55-70%. There was no change in the activity of complex I, II/III, or IV or of citrate synthase in cortex. Similarly, there was no alteration of mitochondrial or cytosolic SOD activity. Thioctic acid (50 or 100 mg/kg IP) alone had no effect on cortical GSH levels in control animals and did not reverse the decrease in GSH levels produced by unilateral or bilateral ICV BSO administration. Thioctic acid (50 or 100 mg/kg IP) had no overall effect on complex I, II/III, or IV or on citrate synthase activity in control animals. Thioctic acid also did not alter cortical mitochondrial respiratory enzyme activity in BSO-treated rats. At the lower dose, thioctic acid tended to increase mitochondrial and cytosolic SOD activity in control animals and in BSO-treated rats. However, at the higher dose, thioctic acid tended to decrease mitochondrial SOD activity. Overall, there was no consistent effect of thioctic acid (50 or 100 mg/kg IP) on SOD activity in control or BSO-treated animals. This study shows that BSO-induced glutathione deficiency does not lead to alterations in mitochondrial respiratory enzyme activity or to changes in SOD activity. GSH depletion in Parkinson's disease therefore may not account for the alterations occurring in complex I and mitochondrial SOD in substantia nigra. Thioctic acid did not alter brain GSH levels or mitochondrial function. Interestingly, however, it did produce some alterations in SOD activity, which may reflect either its antioxidant activity or its ability to act as a thiol-disulphide redox couple.
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PMID:Mitochondrial respiratory enzyme function and superoxide dismutase activity following brain glutathione depletion in the rat. 898 27

The effect of endurance training on glutathione (GSH) status and antioxidant enzyme system was investigated in skeletal muscle, heart, and liver of female Sprague-Dawley rats pair fed an isocaloric diet. Ten weeks of treadmill training (25 m/min, 10% grade for 2 h/day, 5 days/wk) increased citrate synthase activity in the deep vastus lateralis (DVL) and soleus muscles by 79 and 39%, respectively (P < 0.01), but not in the heart or liver. In DVL, GSH content was increased 33% (P < 0.05) with training, accompanied by a 64% (P < 0.05) increase in glutamate content but no change in cysteine. Trained rats showed a 62 and 27% higher GSH peroxidase (GPX) and superoxide dismutase (SOD) activity, respectively (P < 0.05), in DVL compared with control rats. In contrast, GSH content and glutathione reductase (GR) activity in soleus declined with training (P < 0.05), whereas activities of GPX and SOD remained unchanged. Training did not alter GSH status in the liver or plasma but significantly decreased the GSH-to glutathione disulfide ratio in the heart. In addition, GR activity in the liver and GSH sulfur-transferase activity in the heart and DVL were significantly lower in the trained vs control rats DVL muscle had threefold higher gamma-glutamyl transpeptidase activity compared with other tissues; however no significant alteration was observed in the activity of gamma-glutamyltranspeptidase or gamma-glutamylcysteine synthetase in the liver, heart, or skeletal muscle. These data indicate that endurance training can cause tissue- and muscle fiber-specific adaptation of antioxidant systems and that GSH homeostasis in extrahepatic tissues may be determined by utilization and uptake of GSH via the gamma-glutamyl cycle.
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PMID:Adaptations of glutathione antioxidant system to endurance training are tissue and muscle fiber specific. 903 30

This work examines the hypothesis that beetle bioluminescent reactions may primarily have evolved to provide an auxiliary O2 detoxifying mechanism. The activities of antioxidant enzymes and of luciferase in the prothorax (bright) and abdomen (dim) of luminous larval Pyrearinus termitilluminans (Coleoptera: Elateridae) were measured after previous challenge with either hyperoxia, hypoxia, or the firefly luciferase inhibitor luciferin 6'-methyl ether (LME). Upon exposure to pure O2 for 72 h, the prothorax activities of total superoxide dismutase (SOD) and catalase were found to increase by 85% and 50%, respectively. Concomitantly, levels of luciferase and luciferin increased 80% and 50%. Assays of thiobarbituric acid reactive substances (TBARS) showed significantly augmented lipid peroxidation only in the abdomen (30%) where levels of antioxidant enzymes and especially luciferase are low. In contrast, exposure to hypoxia (2% O2) led to significant increases in prothorax citrate synthase (85%), succinate dehydrogenase (25%), and lactate dehydrogenase (30%) activities, but not in luciferase or antioxidant enzyme levels. LME administration alone decreased luciferase activities 20% but did not alter prothorax SOD activity. Prothorax SOD activity was increased by concomitant LME and hyperoxia treatments (30%), along with higher levels of TBARS (25%) and protein reactive carbonyl groups (50%). Altogether these data suggest that in elaterids, bioluminescence and reactions catalyzed by antioxidant enzymes may cooperate to minimize oxidative stress.
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PMID:Bioluminescence as a possible auxiliary oxygen detoxifying mechanism in elaterid larvae. 958 7

Thiobarbituric acid reactant substances (TBARs) content, and the activities of glucose-6-phosphate dehydrogenase (G6PDh), citrate synthase (CS), Cu/Zn- and Mn-superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX) were measured in the lymphoid organs (thymus, spleen, and mesenteric lymph nodes (MLN)) and skeletal muscles (gastrocnemius and soleus) of adrenodemedullated (ADM) rats. The results were compared with those obtained for sham-operated rats. TBARs content was reduced by adrenodemedullation in the lymphoid organs (MLN) (28%), thymus (40%) and spleen (42%)) and gastrocnemius muscle (67%). G6PDh activity was enhanced in the MLN (69%) and reduced in the spleen (28%) and soleus muscle (75%). CS activity was reduced in all tissues (MLN (75%), spleen (71%), gastrocnemius (61%) and soleus (43%)), except in the thymus which displayed an increment of 56%. Cu/Zn-SOD activity was increased in the MLN (126%), thymus (223%), spleen (80%) and gastrocnemius muscle (360%) and was reduced in the soleus muscle (31%). Mn-SOD activity was decreased in the MLN (67%) and spleen (26%) and increased in the thymus (142%), whereas catalase activity was reduced in the MLN (76%), thymus (54%) and soleus muscle (47%). It is particularly noteworthy that in ADM rats the activity of glutathione peroxidase was not detectable by the method used. These data are consistent with the possibility that epinephrine might play a role in the oxidative stress of the lymphoid organs. Whether this fact represents an important mechanism for the establishment of impaired immune function during stress remains to be elucidated.
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PMID:Changes in the TBARs content and superoxide dismutase, catalase and glutathione peroxidase activities in the lymphoid organs and skeletal muscles of adrenodemedullated rats. 969 30

Pre-eclampsia is a hypertensive disorder of human pregnancy that is a leading cause of premature delivery and fetal growth retardation. It is characterized by hypertension, reduced uteroplacental blood flow, proteinuria and oedema. Pre-eclampsia is associated with increased lipid peroxidation in the maternal circulation and in the placenta. Mitochondria are sources of oxygen radicals and are enriched with polyunsaturated fatty acids that are susceptible to peroxidation. Therefore, the mitochondria could be an important source of oxidative stress and lipid peroxidation. To study this, the level of lipid peroxidation in the mitochondrial fraction of placentae obtained from normally pregnant women (n=8) and women with pre-eclampsia (n=8) was examined. Placental tissues were homogenized and the mitochondrial fraction was isolated by ultracentrifugation. Mitochondrial lipid peroxides were estimated by malondialdehyde (MDA). NADPH and Fe++ were used to stimulate lipid peroxidation. Superoxide dismutase (SOD) was used to inhibit superoxide radicals and mannitol to inhibit hydroxyl radicals. The following results were found: (1) MDA levels were significantly greater in the mitochondrial fraction isolated from pre-eclamptic placentae than from normal placentae (27.4+/-3.0 versus 17.0+/-1.8 nmol/g tissue, mean+/-s.e., P<0.05); (2) the oxidative potential of the pre-eclamptic mitochondrial fraction was also higher than normal as evidenced by the significantly greater stimulation of lipid peroxidation by NADPH and Fe+ + (248+/-25 versus 164+/-35 nmol/g, P<0.05); (3) superoxide dismutase, but not mannitol, attenuated the lipid peroxidation induced by NADPH and Fe+ + demonstrating that superoxide is the radical responsible for mitochondrial lipid peroxidation in this system; and (4) the amount of mitochondrial protein was 47 per cent greater and the activity of the mitochondrial enzyme, citrate synthase, was 56 per cent greater in the pre-eclamptic placentae indicating an increase in the amount of mitochondria in the pre-eclamptic placentae. It is concluded that: (1) mitochondrial lipid peroxidation is increased in pre-eclampsia; (2) the amount of placental mitochondria is increased in pre-eclampsia; (3) placental mitochondria contribute to the abnormal increase in lipid peroxidation that occurs in pre-eclamptic placentae by both an increase in their amount and an increase in their susceptibility to oxidation; and (4) mitochondrial generation of superoxide could be an important source of oxidative stress in pre-eclampsia.
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PMID:Placental mitochondria as a source of oxidative stress in pre-eclampsia. 985 61

The effects of endurance training on gene expression of superoxide dismutase (SOD) and glutathione peroxidase (GPX) were investigated in type 2a and 2b skeletal muscles, as well as heart and liver, in the rat. Female Sprague-Dawley rats (4 months old, 300-320 g) were randomly divided into a trained (T, n = 11) and a control (C, n = 10) group and were pair fed a diet consisting of 66% cornstarch and 34% basal diet that contained all essential nutrients. Training was conducted on a treadmill at 25 m x min(-1), 10% grade for 2 h per day, 5 days per week for 10 weeks, resulting in a 79% (p < 0.01) increase in citrate synthase activity in the deep portion of vastus lateralis muscle (DVL, type 2a). Cu-Zn SOD activity was 35% higher (p < 0.01) in DVL of T versus C rats, and Cu-Zn SOD mRNA abundance showed a 125% increase with training (p < 0.05). Cu-Zn SOD protein content was not altered in DVL, but increased significantly (p < 0.05) in the superficial portion of vastus lateralis (type 2b) with training. Trained rats showed a 66% higher (p < 0.05) Mn SOD protein content in DVL, but Mn SOD activity and mRNA abundance were not affected. Training also significantly increased GPX activity by 62% (p < 0.05), without changing its mRNA abundance, in the DVL. Heart and liver showed a 112 and 58% increase (p < 0.01) in Cu-Zn SOD mRNA abundance with training, respectively, but no other training adaptation was detected. These data indicate that endurance training can promote gene expression of muscle antioxidant enzymes in a fiber-specific manner. Training appears to upregulate Cu-Zn SOD mRNA abundance in a number of aerobic tissues, whereas Mn SOD and GPX induction observed in DVL may occur at the post-transcriptional levels.
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PMID:Endurance training alters antioxidant enzyme gene expression in rat skeletal muscle. 1032 36

Huntington's disease (HD) is a hereditary neurodegenerative disorder presenting with chorea, dementia, and extensive striatal neuronal death. The mechanism through which the widely expressed mutant HD gene mediates a slowly progressing striatal neurotoxicity is unknown. Glutamate receptor-mediated excitotoxicity has been hypothesized to contribute to the pathogenesis of HD. Here we show that transgenic HD mice expressing exon 1 of a human HD gene with an expanded number of CAG repeats (line R6/1) are strongly protected from acute striatal excitotoxic lesions. Intrastriatal infusions of the N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid caused massive striatal neuronal death in wild-type mice, but no damage in transgenic HD littermates. The remarkable neuroprotection in transgenic HD mice occurred at a stage when they had not developed any neurological symptoms caused by the mutant HD gene. At this stage there was no change in the number of striatal neurons and astrocytes in untreated R6/1 mice, although the striatal volume was decreased by 17%. Moreover, transgenic HD mice had normal striatal levels of NMDA receptors, calbindin D28k (calcium buffer), superoxide dismutase activity (antioxidant enzyme), Bcl-2 (anti-apoptotic protein), heat shock protein 70 (stress-induced anti-apoptotic protein), and citrate synthase activity (mitochondrial enzyme). We propose that the presence of exon 1 of the mutant HD gene induces profound changes in striatal neurons that render these cells resistant to excessive NMDA receptor activation.
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PMID:Transgenic mice expressing a Huntington's disease mutation are resistant to quinolinic acid-induced striatal excitotoxicity. 1041 43

The effects of endurance training on the enzyme activity, protein content, and mRNA abundance of Mn and CuZn superoxide dismutase (SOD) were studied in various phenotypes of rat skeletal muscle. Female Sprague-Dawley rats were randomly divided into trained (T, n = 8) and untrained (U, n = 8) groups. Training, consisting of treadmill running at 27 m/min and 12% grade for 2 h/day, 5 days/wk for 10 wk, significantly increased citrate synthase activity (P < 0. 01) in the type I (soleus), type IIa (deep vastus lateralis, DVL), and mixed type II (plantaris) muscles but not in type IIb (superficial vastus lateralis, SVL) muscle. Mitochondrial (Mn) SOD activity was elevated by 80% (P < 0.05) with training in DVL. SVL and plantaris muscle in T rats showed 54 and 42% higher pooled immunoreactive Mn SOD protein content, respectively, than those in U rats. However, no change in Mn SOD mRNA level was found in any of the muscles. CuZn SOD activity, protein content, and mRNA level in general were not affected by training, except for a 160% increase in pooled CuZn SOD protein in SVL. Training also significantly increased glutathione peroxidase and catalase activities (P < 0.05), but only in DVL muscle. These data indicate that training adaptations of Mn SOD and other antioxidant enzymes occur primarily in type IIa fibers, probably as a result of enhanced free radical generation and modest antioxidant capacity. Differential training responses of mRNA, enzyme protein, and activity suggest that separate cellular signals may control pre- and posttranslational regulation of SOD.
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PMID:Superoxide dismutase gene expression in skeletal muscle: fiber-specific adaptation to endurance training. 1048 4

The effect of the induction of i-NOS in primary glial cultures was studied with respect to the protein levels of reactive oxygen species (ROS) scavenging enzymes and the cytotoxicity of nitric oxide (.NO) formation at different levels of artificially generated superoxide. Stimulation of the cultures by bacterial lipopolysaccharides and gamma-interferon resulted in an induction of i-NOS exclusively in microglial cells. Among the ROS scavenging enzymes superoxide dismutase (Cu/Zn- and Mn-isoform), glutathione peroxidase and catalase only mitochondrial Mn-SOD was found to be upregulated in the course of i-NOS induction (Western blots). Although .NO formation did not affect cell viability at physiological levels of superoxide over a time period of 4 days, it caused an oxidative load particularly in microglial cells as observed by monitoring the oxidation of dichloro-dihydrofluorescein, an indicator for the formation of peroxynitrite and ROS. Elevated levels of superoxide, generated either intracellularly by paraquat or extracellularly via xanthine oxidase and hypoxanthine, resulted dose-dependently in a larger decline of cell viability in the .NO forming cultures compared to controls (release of lactate dehydrogenase, citrate synthase, stainability by propidium iodide, and tetramethylrhodamine). NOS-inhibitors reduced the degree of cell damage to that seen for control cultures, indicating an ONOO--/.NO mediated mechanism of cell damage. Our data support the concept that i-NOS catalyzed .NO-formation leads to an ONOO--mediated increased oxidative load. At physiological levels of superoxide and within a wide range of higher superoxide levels this nitrosative stress is well balanced in cultured glial cells by protective mechanisms.
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PMID:Peroxynitrite mediated damage and lowered superoxide tolerance in primary cortical glial cultures after induction of the inducible isoform of NOS. 1049 18

These experiments tested the hypothesis that short-term endurance exercise training would rapidly improve (within 5 days) the diaphragm oxidative/antioxidant capacity and protect the diaphragm against contraction-induced oxidative stress. To test this postulate, male Sprague-Dawley rats (6 weeks old) ran on a motorized treadmill for 5 consecutive days (40-60 min x day(-1)) at approximately 65% maximal oxygen uptake. Costal diaphragm strips were excised from both sedentary control (CON, n=14) and trained (TR, n=13) animals 24 h after the last exercise session, for measurement of in vitro contraction properties and selected biochemical parameters of oxidative/antioxidant capacity. Training did not alter diaphragm force-frequency characteristics over a full range of submaximal and maximal stimulation frequencies (P > 0.05). In contrast, training improved diaphragm resistance to fatigue as contraction forces were better-maintained by the diaphragms of the TR animals during a submaximal 60-min fatigue protocol (P < 0.05). Following the fatigue protocol, diaphragm strips from the TR animals contained 30% lower concentrations of lipid hydroperoxides compared to CON (P < 0.05). Biochemical analysis revealed that exercise training increased diaphragm oxidative and antioxidant capacity (citrate synthase activity +18%, catalase activity +24%, total superoxide dismutase activity +20%, glutathione concentration +10%) (P < 0.05). These data indicate that short-term exercise training can rapidly elevate oxidative capacity as well as enzymatic and non-enzymatic antioxidant defenses in the diaphragm. Furthermore, this up-regulation in antioxidant defenses would be accompanied by a reduction in contraction-induced lipid peroxidation and an increased fatigue resistance.
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PMID:Short-term exercise training improves diaphragm antioxidant capacity and endurance. 1055 69


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