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)

We evaluated a simplified method for preparation and analysis of platelet cytochrome c oxidase activity in Alzheimer's disease (AD) and control patients. Mean cytochrome c oxidase activity in controls (n = 17) was 0.233 sec-1/mg whereas mean cytochrome c oxidase activity in Alzheimer patients (n = 19) was 0.193 sec-1/mg, p = 0.033. Complex III (ubiquinol:cytochrome c oxidoreductase), complex II (succinic dehydrogenase), and citrate synthase were all assayed as internal controls and were not significantly different in controls and Alzheimer patients. There is a relatively specific loss of platelet cytochrome c oxidase activity in Alzheimer disease patients.
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PMID:Reduced platelet cytochrome c oxidase activity in Alzheimer's disease. 761 12

We compared the thiamine and thiamine phosphate contents in the frontal, temporal, parietal, and occipital cortex of six patients with frontal lobe degeneration of the non-Alzheimer's type (FNAD) or frontotemporal dementia with five age-, postmortem delay-, and agonal status-matched control subjects. Our results reveal a 40-50% decrease in thiamine diphosphate (TDP) in the cortex of FNAD patients, whereas thiamine monophosphate was increased 49-119%. TDP synthesizing and hydrolyzing enzymes were unaffected. The activity of citrate synthase, a mitochondrial marker enzyme, was decreased in the frontal cortex of patients with FNAD, but no correlation with TDP content was found. These results suggest that decreased contents of TDP, which is essentially mitochondrial, is a specific feature of FNAD. As TDP is an essential cofactor for oxidative metabolism and neurotransmitter synthesis, and because low thiamine status (compared with other species) is a constant feature in humans, a nearly 50% decrease in cortical TDP content may contribute significantly to the clinical symptoms observed in FNAD. This study also provides a basis for a trial of thiamine, to improve the cognitive status of the patients.
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PMID:Low thiamine diphosphate levels in brains of patients with frontal lobe degeneration of the non-Alzheimer's type. 934 45

A rapid method (about 1.5 h) for the isolation of intact functional mitochondria from neurons and astrocytes in primary culture is described. Mitochondria isolated by this method are metabolically active and tightly coupled as shown by respiratory control ratio values, which were about 4 with glutamate-malate as substrate. The activities of marker enzymes revealed the occurrence of a low degree of cytosolic (5%) or synaptosomal (5.5%) contamination in the mitochondrial fractions. In addition, the activity of citrate synthase was increased by 4 fold in both neuronal and astrocytic mitochondria with respect to values found in cell homogenates. These results confirm that the method affords mitochondrial preparations from cultured brain cells at suitable levels of purity and enrichment for the study of their mitochondrial function. Since mitochondrial damage has been associated with the pathogenesis of certain neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases (P. Chagnon, C. Betard, Y. Robitaille, A. Cholette, D. Gauvreau, Distribution of brain cytochrome oxidase activity in various neurodegenerative disease, Neuroreport 6 (1995) 711-715 [6]; S.J. Kish, C. Bergeron, A. Rajput, S. Dozic, F. Mastrogiacomo, L. Chang, J.M. Wilson, L.M. DiStefano, J.N. Nobrega, Brain cytochrome oxidase in Alzheimer's disease, J. Neurochem. 59 (1992) 776-779 [10]; A.H.V. Schapira, J.M. Cooper, D. Dexter, J.B. Clark, P. Jenner, C.D. Marsden, Mitochondrial complex I deficiency in Parkinson's disease, J. Neurochem. 54 (1990) 823-827 [15]), the method described here shed light on the possible susceptibility of neuronal or astrocytic mitochondria to deleterious effects of these diseases.
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PMID:A rapid method for the isolation of metabolically active mitochondria from rat neurons and astrocytes in primary culture. 950 34

Defects in mitochondrial oxidative metabolism, in particular decreased activity of cytochrome c oxidase, have been demonstrated in Alzheimer's disease, and after the expression of the amyloid precursor protein (APP) in cultured cells, suggesting that mitochondria might be involved in beta-amyloid toxicity. Recent evidence suggests that the proteolysis of APP to generate beta-amyloid is at least in part intracellular, preceding the deposition of extracellular fibrils. We have therefore investigated the effect of incubation of isolated rat brain mitochondria with the beta-amyloid fragment 25-35 (100 microM) on the activities of the mitochondrial respiratory chain complexes I, II-III, IV (cytochrome c oxidase) and citrate synthase. The peptide caused a rapid, dose-dependent decrease in the activity of complex IV, white it had no effect on the activities on any of the other enzymes tested. The reverse sequence peptide (35-25) had no effect on any of the activities measured. We conclude that inhibition of mitochondrial complex IV might be a contributing factor to the pathogenesis of Alzheimer's disease.
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PMID:beta-Amyloid fragment 25-35 selectively decreases complex IV activity in isolated mitochondria. 1048 79

To assess mitochondrial function and test the hypothesis of an underlying oxidative phosphorylation defect in Alzheimer disease (AD), we evaluated the activities of mitochondrial respiratory chain enzyme complexes I+III, complexes II+III, complex IV (cytochrome c oxidase, COX), succinate dehydrogenase, and citrate synthase in the frontal cortex, temporal cortex, hippocampus, and cerebellum of 23 AD patients and 13 normal human brains. The major finding was a significant decrease in COX activity in AD temporal cortex and hippocampus, both whether activities were expressed per noncollagen protein content (49 +/-4.6 versus 78+/-10.8 nmol/min/mg NCP, P = 0.006; 23+/-1.9 versus 48.6+/-8.1 nmol/min/mg NCP, p = 0.003) or corrected for citrate synthase activity (1.6+/-0.2 versus 3+/-0.4, P = 0.001; 0.76+/-0.1 versus 1.76+/-0.26, P = 0.0009). There were no significant differences in the activities of complexes I+III, II+III, and of succinate dehydrogenase in any of the brain regions examined. Our results suggest a specific defect of COX in the AD brain versus the normal human brain, which may contribute to impaired energy generation. Biochemically, the defect is confined to selected brain regions, suggesting anatomic specificity.
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PMID:A selective defect of cytochrome c oxidase is present in brain of Alzheimer disease patients. 1085 95

Oxidative stress and mitochondrial dysfunction have been linked to neurodegenerative disorders such as Parkinson's and Alzheimer's disease. However, it is not yet understood how endogenous mitochondrial oxidative stress may result in mitochondrial dysfunction. Most prior studies have tested oxidative stress paradigms in mitochondria through either chemical inhibition of specific components of the respiratory chain, or adding an exogenous insult such as hydrogen peroxide or paraquat to directly damage mitochondria. In contrast, mice that lack mitochondrial superoxide dismutase (SOD2 null mice) represent a model of endogenous oxidative stress. SOD2 null mice develop a severe neurological phenotype that includes behavioral defects, a severe spongiform encephalopathy, and a decrease in mitochondrial aconitase activity. We tested the hypothesis that specific components of the respiratory chain in the brain were differentially sensitive to mitochondrial oxidative stress, and whether such sensitivity would lead to neuronal cell death. We carried out proteomic differential display and examined the activities of respiratory chain complexes I, II, III, IV, V, and the tricarboxylic acid cycle enzymes alpha-ketoglutarate dehydrogenase and citrate synthase in SOD2 null mice in conjunction with efficacious antioxidant treatment and observed differential sensitivities of mitochondrial proteins to oxidative stress. In addition, we observed a striking pattern of neuronal cell death as a result of mitochondrial oxidative stress, and were able to significantly reduce the loss of neurons via antioxidant treatment.
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PMID:Endogenous mitochondrial oxidative stress: neurodegeneration, proteomic analysis, specific respiratory chain defects, and efficacious antioxidant therapy in superoxide dismutase 2 null mice. 1472 Feb 15

1. Cerebral vessels express oestrogen receptors (ER) in both the smooth muscle and endothelial cell layers of cerebral blood vessels. Levels of ERalpha are higher in female rats chronically exposed to oestrogen, either endogenous or exogenous. 2. Chronic exposure to oestrogen, either endogenous (normally cycling females) or exogenous (ovariectomized with oestrogen replacement), results in cerebral arteries that are more dilated than arteries from ovariectomized counterparts when studied in vitro. This effect is primarily mediated by an increase in the production of vasodilator factors, including nitric oxide (NO) and prostacylin. In contrast, oestrogen appears to suppress the production of endothelial-derived hyperpolarizing factor. Oestrogen treatment increases cerebrovascular levels of endothelial nitric oxide synthase (eNOS), cyclo-oxygenase (COX)-1 and prostacyclin synthase. In addition, via activation of the phosphatidylinositol 3-kinase/Akt pathway, both acute and chronic oestrogen exposure increases eNOS phosphorylation, increasing NO production. 3. Oestrogen receptors have also been localized to cerebrovascular mitochondria and exposure to oestrogen increases the efficiency of energy production while simultaneously reducing mitochondrial production of reactive oxygen species. Oestrogen increases the production of mitochondrial proteins encoded by both mitochondrial and nuclear DNA, including cytochrome c, subunits I and IV of complex IV and Mn-superoxide dismutase. Oestrogen treatment increases the activity of citrate synthase and complex IV and decreases mitochondrial production of H(2)O(2). 4. Oestrogen also has potent anti-inflammatory effects in the cerebral circulation that may have important implications for the incidence and severity of cerebrovascular disease. Administration of lipopolysaccharide or interleukin-1beta to ovariectomized female rats induces cerebrovascular COX-2 and inducible nitric oxide synthase (iNOS) protein expression and increases prostaglandin E(2) expression. Levels of COX-2 and iNOS expression vary with the stage of the oestrous cycle, and the cerebrovascular inflammatory response is suppressed in ovariectomized animals treated with oestrogen. Interleukin-1beta induction of COX-2 protein is prevented by treatment with a nuclear factor (NF)-kappaB inhibitor, and oestrogen treatment reduces cerebrovascular NF-kappaB activity. 5. Cerebrovascular dysfunction and pathology contribute to the pathogenesis of stroke, brain trauma, oedema and dementias, such as Alzheimer's disease. A better understanding of the action of oestrogen on cerebrovascular function holds promise for the development of new therapeutic entities that could be useful in preventing or treating a wide variety of cerebrovascular diseases.
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PMID:Cerebrovascular effects of oestrogen: multiplicity of action. 1760 May 62

Human HtrA2 is part of the HtrA family of ATP-independent serine proteases that are conserved in both prokaryotes and eukaryotes and localizes to the intermembrane space of the mitochondria. Several recent reports have suggested that HtrA2 is important for maintaining proper mitochondrial homeostasis and may play a role in Alzheimer's disease (AD), which is characterized by the presence of aggregates of the amyloid-beta peptide 1-42 (Abeta1-42). In this study, we analyzed the ability of HtrA2 to delay the aggregation of the model substrate citrate synthase (CS) and of the toxic Abeta1-42 peptide. We found that HtrA2 had a moderate ability to delay the aggregation of CS in vitro, and this activity was significantly enhanced when the PDZ domain was removed suggesting an inhibitory role for this domain on the activity. Additionally, using electron microscopy and nuclear magnetic resonance analyses, we observed that HtrA2 significantly delayed the aggregation of the Abeta1-42 peptide. Interestingly, the protease activity of HtrA2 and its PDZ domain were not essential for the delay of Abeta1-42 peptide aggregation. These results indicate that besides its protease activity, HtrA2 also performs a chaperone function and suggest a role for HtrA2 in the metabolism of intracellular Abeta and in AD.
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PMID:A new function of human HtrA2 as an amyloid-beta oligomerization inhibitor. 1950 9

It has been suggested that the lateralization of the human brain underlies hemispheric specialization and that it can be observed also on a biochemical level. Biochemical laterality appears to be a basis of volumetric or functional asymmetry but direct relationships among them are still unclear. Moreover, age-related differences between the right and left hemispheres are not well documented in various rat strains. In the current study, biochemical markers sensitive to Alzheimer disease (activities of high-affinity choline uptake and of nitric oxide synthases, expression of 17beta-hydroxysteroid dehydrogenase type 10) were estimated in both hemispheres of young and old male Wistar/Long Evans rats. Our experiments indicate (1) differences in some biochemical markers between young Wistar and Long Evans rats (the activities of endothelial nitric oxide synthase are higher in Long Evans and those of citrate synthase in Wistar rats), (2) more similar brain asymmetry of healthy human/young Wistar brains when compared to those of young Long Evans, (3) the decrease in asymmetry of the physiologically left/right lateralized biomarker during aging (the activity of the high-affinity choline uptake decreases more markedly in the left side of old Wistar rats) in accordance with the HAROLD model, (4) the age-related shift to reversed left/right asymmetry of the physiologically right/left lateralized biomarker (the activity of inducible nitric oxide synthase increases especially in the left side of old Long Evans rats), and finally (5) age-related differences in physiologically unlateralized biomarkers between Wistar and Long Evans rats (changes in the activities of neural/endothelial nitric oxide synthases or in expression of 17beta-hydroxysteroid dehydrogenase type 10 are more asymmetrical in old Wistar when compared to rather bilateral alterations of old Long Evans animals). It seems that the physiological lateralization of the human or rat brains on a biochemical level and their age-related alterations are dependent on biomarker type/function. By our opinion, it is difficult, perhaps impossible, to make one simple universal model, at least on a biochemical level. Since lateral analyses are of sufficient sensitivity to reveal subtle links, we recommend using Wistar rather than Long Evans rats in modeling of diseases accompanied by alterations in brain asymmetry.
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PMID:Aging and lateralization of the rat brain on a biochemical level. 2036 89

Bilobalide (BB), a sesquiterpene trilactone from Ginkgo biloba has been proposed to have protective effects on mitochondrial function. Using ovariectomized rats to mimic the post-menopausal pathophysiological changes in women, this study demonstrated that BB treatment could prevent estrogen withdrawal-induced decrease in mitochondrial adenosine triphosphate content, cytochrome c oxidase subunit I (COXI) mRNA and protein levels and COX activity in hippocampal tissues as effectively as estradiol benzoate. But neither ovariectomy nor BB treatment affected citrate synthase activity. These results suggested that BB was able to regulate COX activity via up-regulation of the gene and protein expression of its mitochondrial DNA-coded subunits, and modulation of COX activity by BB might contribute to its protective effects on mitochondrial function. Given that ovariectomy induces decrease in estrogen levels similar to that of menopause, BB may be useful in developing therapy for neurodegenerative diseases such as Alzheimer's disease in post-menopausal females.
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PMID:Bilobalide protects mitochondrial function in ovariectomized rats by up-regulation of mRNA and protein expression of cytochrome c oxidase subunit I. 2049 Jul 13


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