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)

Amitriptyline is a tricyclic antidepressant widely used in the treatment of chronic pain. The objective of the present study was to investigate the potential cytotoxic effects of amitriptyline in human fibroblasts primary culture. Human fibroblast cells were cultured from healthy subjects and incubated with 50 microM and 100 microM amitriptyline. Cell counting was performed to study dose-dependency of toxicity. Lipid peroxidation analysis and western blotting for antioxidants catalase and mitochondrial superoxide dismutase (MnSOD) were carried out in order to evaluate oxidative stress. To investigate mitochondria damage the following determinations were made: cytochrome c, citrate synthase, and mitochondrial membrane potential (DeltaPsi(m)). Amitriptyline reduced significantly the number of cultured cells, resulting in a decrease of 45.2%, 65.0% and 94.9% when treated with 20 microM, 50 microM and 100 microM amitriptyline, respectively. This drug enhanced the production of oxidized products during lipid peroxidation, inverting the reduced/oxidized ratio to 25% reduction and 75% oxidation after 24h of amitriptyline administration. A decreased in catalase protein levels has been also observed. Moreover, amitriptyline treatment induced a significant decrease of cytochrome c, DeltaPsi(m), and citrate synthase activity; revealing mitochondrial damage. These findings suggest that amitriptyline has a strong cytotoxic effect in human fibroblasts, decreasing growth rate and mitochondrial activity, and increasing oxidative stress.
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PMID:Cytotoxic effects of amitriptyline in human fibroblasts. 1798 Apr 74

Dendritic cells (DC) are potent antigen-presenting cells capable of inducing T and B responses and immune tolerance. We have characterized some aspects of energy metabolism accompanying the differentiation process of human monocytes into DC. Compared to precursor monocytes, DC exhibited a much larger number of mitochondria and consistently (i) a higher endogenous respiratory activity and (ii) a more than sixfold increase in ATP content and an even larger increase in the activity of the mitochondrial marker enzyme citrate synthase. The presence in the culture medium of rotenone, an inhibitor of the respiratory chain Complex I, prevented the increase in mitochondrial number and ATP level, without affecting cell viability. Rotenone inhibited DC differentiation, as revealed by the observation that the expression of CD1a, which is a specific surface marker of DC differentiation, was strongly reduced. Cells cultured in the presence of rotenone displayed a lower content of growth factor-induced, mitochondrially generated, hydrogen peroxide. A similar drop in ROS was observed upon addition of catalase, which caused functional effects similar to those produced by rotenone treatment. These results suggest that ROS play a crucial role in DC differentiation and that mitochondria are an important source of ROS in this process.
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PMID:Role of mitochondria and reactive oxygen species in dendritic cell differentiation and functions. 1824 95

The ocean quahog Arctica islandica is the longest-lived of all bivalve and molluscan species on earth. Animals close to 400 years are common and reported maximum live span around Iceland is close to 400 years. High and stable antioxidant capacities are a possible strategy to slow senescence and extend lifespan and this study has investigated several antioxidant parameters and a mitochondrial marker enzyme in a lifetime range spanning from 4-200 years in the Iceland quahog. In gill and mantle tissues of 4-192 year old A. islandica, catalase, citrate synthase activity and glutathione concentration declined rapidly within the first 25 years, covering the transitional phase of rapid somatic growth and sexual maturation to the outgrown mature stages (approximately 32 years). Thereafter all three parameters kept rather stable levels for > 150 years. In contrast, superoxide dismutase activities maintained high levels throughout life time. These findings support the 'Free Radical-Rate of Living theory', antioxidant capacities of A. islandica are extraordinarily high and thus may explain the species long life span.
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PMID:Imperceptible senescence: ageing in the ocean quahog Arctica islandica. 1848 11

The aim of this study was to investigate the effect of different protocols of physical exercise on oxidative stress markers in mouse liver. Twenty-eight male CF1 mice (30-35 g) were distributed into 4 groups (n = 7) - untrained (UT), continuous running (CR), downhill running (D-HR), and intermittent running (IR) - and underwent an 8-week training program. Forty-eight hours after the last training session, the animals were killed, and their livers were removed. Blood lactate, creatine kinase, citrate synthase, thiobarbituric acid reactive species, carbonyl, superoxide dismutase (SOD), and catalase (CAT) activities were assayed. Results show a decrease in the level of lipoperoxidation and protein carbonylation in the CR and D-HR groups. SOD activity was significantly increased and CAT activity was reduced in the CR and D-HR groups. Our findings indicate that CR and D-HR may be important for decreasing oxidative damage and in the regulation of antioxidant enzymes (SOD and CAT) in the livers of trained mice.
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PMID:Effect of different models of physical exercise on oxidative stress markers in mouse liver. 1923 86

Fatty liver has been linked to low aerobic fitness, but the mechanisms are unknown. We previously reported a novel model in which rats were artificially selected to be high capacity runners (HCR) and low capacity runners (LCR) that in a sedentary condition have robustly different intrinsic aerobic capacities. We utilized sedentary HCR/LCR rats (generation 17; max running distance equalled 1514 +/- 91 vs. 200 +/- 12 m for HCR and LCR, respectively) to investigate if low aerobic capacity is associated with reduced hepatic mitochondrial oxidative capacity and increased susceptibility to hepatic steatosis. At 25 weeks of age, LCR livers displayed reduced mitochondrial content (reduced citrate synthase activity and cytochrome c protein) and reduced oxidative capacity (complete palmitate oxidation in hepatic mitochondria (1.15 +/- 0.13 vs. 2.48 +/- 1.1 nm g(-1) h, P < 0.0001) and increased peroxisomal activity (acyl CoA oxidase and catalase activity) compared to the HCR. The LCR livers also displayed a lipogenic phenotype with higher protein content of both sterol regulatory element binding protein-1c and acetyl CoA carboxylase. These differences were associated with hepatic steatosis in the LCR including higher liver triglycerides (6.00 +/- 0.71 vs. 4.20 +/- 0.39 nmol g(-1), P = 0.020 value), >2-fold higher percentage of hepatocytes associated with lipid droplets (54.0 +/- 9.2 vs. 22.0 +/- 3.5%, P = 0.006), and increased hepatic lipid peroxidation compared to the HCR. Additionally, in rats aged to natural death, LCR livers had significantly greater hepatic injury (fibrosis and apoptosis). We provide novel evidence that selection for low intrinsic aerobic capacity causes reduced hepatic mitochondrial oxidative capacity that increases susceptibility to both hepatic steatosis and liver injury.
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PMID:Rats selectively bred for low aerobic capacity have reduced hepatic mitochondrial oxidative capacity and susceptibility to hepatic steatosis and injury. 1936 5

Emerging evidence indicates that impaired mitochondrial fatty acid beta-oxidation plays a key role in liver steatosis. We have recently demonstrated that increased angiotensin (ANG) II causes progressive hepatic steatosis associated with oxidative stress; however, the underlying mechanisms remain unclear. We hypothesized that ANG II causes hepatic mitochondrial oxidative damage and impairs mitochondrial beta-oxidation, thereby leading to hepatic steatosis. We used the Ren2 rat with elevated endogenous ANG II levels to evaluate mitochondrial ultrastructural changes, gene expression levels, and beta-oxidation. Compared with Sprague-Dawley littermates, Ren2 livers exhibited mitochondrial damage and reduced beta-oxidation, as evidenced by ultrastructural abnormalities, decrease of mitochondrial content, percentage of palmitate oxidation to CO(2), enzymatic activities (beta-HAD and citrate synthase), and the expression levels of cytochrome c, cytochrome c oxidase subunit 1, and mitochondrial transcription factor A. These abnormalities were improved with either ANG II receptor blocker valsartan or superoxide dismutase/catalase mimetic tempol treatment. Both valsartan and tempol substantially attenuated mitochondrial lipid peroxidation in Ren2 livers. Interestingly, there was no difference in the expression of key enzymes (ACC1 and FAS) for fatty acid syntheses and their transcription factors (SREBP-1c and ChREBP) between Sprague-Dawley, untreated Ren2, and valsartan- or tempol-treated Ren2 rats. These results document that ANG II induces mitochondrial oxidative damage and impairs mitochondrial beta-oxidation, contributing to liver steatosis.
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PMID:Oxidative stress-mediated mitochondrial dysfunction contributes to angiotensin II-induced nonalcoholic fatty liver disease in transgenic Ren2 rats. 1996 4

Acute exercise in mice induces intestinal lymphocyte (IL) apoptosis. Freewheel running reduces apoptosis and forced exercise training increases splenocyte antioxidant levels. The purpose of this study was to examine the effect of freewheel running and acute exercise on mouse IL numbers and concentrations of apoptosis and antioxidant proteins and pro-inflammatory cytokines in IL. Female C57BL/6 mice had access to in-cage running wheels (RW) or cages without wheels (NRW) for 16 weeks and were randomized at the end of training to no exercise control (TC) or to treadmill exercise with sacrifice after 90 min of running (TREAD; 30 min, 22 m min(-1); 30 min, 25 m min(-1); 30 min, 28 m min(-1); 2 degrees slope). IL were analyzed for pro-(caspase 3 and 7) and anti-(Bcl-2) apoptotic proteins, endogenous antioxidants (glutathione peroxidase: GPx; catalase: CAT) and the pro-inflammatory cytokine, TNF-alpha. RW mice had higher cytochrome oxidase (p<0.001) and citrate synthase (p<0.01) activities in plantaris and soleus muscles and higher GPx and CAT expression in IL (p<0.05) (indicative of training) compared with NRW mice. TNF-alpha expression was lower (p<0.05) and IL numbers higher (p<0.05) in RW vs. NRW mice. No training effect was observed for apoptotic protein expression, although TREAD resulted in higher caspase and lower Bcl-2. These results suggest that freewheel running in mice for 16 weeks enhances antioxidant and reduces TNF-alpha expression in IL but does not reduce pro-apoptotic protein expression after acute exercise. Results are discussed in terms of implications for inflammatory bowel diseases where apoptotic proteins and TNF-alpha levels are elevated.
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PMID:Voluntary exercise training in mice increases the expression of antioxidant enzymes and decreases the expression of TNF-alpha in intestinal lymphocytes. 1948 47

Cold acclimation of ectotherms results typically in enhanced oxidative capacities and lipid remodeling, changes that should increase the risk of lipid peroxidation (LPO). It is unclear whether activities of antioxidant enzymes may respond in a manner to mitigate the increased potential for LPO. The current study addresses these questions using killifish (Fundulus heteroclitus macrolepidotus) and bluegill (Lepomis macrochirus) acclimated to 5 and 25 degrees C for 9 days and 2 months, respectively. Because the effects of temperature acclimation on pro- and antioxidant metabolism may be confounded by variable activity levels among temperature groups, one species (killifish) was also subjected to a 9-day exercise acclimation. Oxidative capacity of glycolytic (skeletal) muscle (indicated by the activity of cytochrome c oxidase) was elevated by 1.5-fold in killifish, following cold acclimation, but was unchanged in cardiac muscle and also unaffected by exercise acclimation in either tissue. No changes in citrate synthase activity were detected in either tissue following temperature acclimation. Enzymatic antioxidants (catalase and superoxide dismutase) of either muscle type were unaltered by temperature or exercise acclimation. Mitochondria from glycolytic muscle of cold-acclimated killifish were enriched in highly oxidizable polyunsaturated fatty acids (PUFA), including diacyl phospholipids (total carbons:total double bonds) 40:8 and 44:12. Increased oxidative capacity, coupled with elevated PUFA content in mitochondria from cold-acclimated animals did not, however, impact LPO susceptibility when measured with C11-BODIPY. The apparent mismatch between oxidative capacity and enzymatic antioxidants following temperature acclimation will be addressed in future studies.
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PMID:Temperature acclimation alters oxidative capacities and composition of membrane lipids without influencing activities of enzymatic antioxidants or susceptibility to lipid peroxidation in fish muscle. 2008 29

In vitro chaperone-like activity of the serpin family member and plasma acute-phase component human alpha(1)-antitrypsin (AAT) has been shown for the first time. Results of light-scattering experiments demonstrated that AAT efficiently inhibits both heat- and chemical-induced aggregation of various test proteins including alcohol dehydrogenase, aldolase, carbonic anhydrase, catalase, citrate synthase, enolase, glutathione S-transferase, l-lactate dehydrogenase, and beta(L)-crystallin. The results suggest that the unique metastable serpin architecture enables dual function, protease inhibiton as well as chaperone activity and highlight the serpin superfamily as a possible source of additional intra- and extracellular chaperones (e.g. alpha(1)-antichymotrypsin). The present finding is surprising in the light of the well-known role of mutated forms of AAT and other serpins in the pathogenesis of diseases called serpinopathies that featured with aberrant conformational transitions and consequent self-aggregation of serpin proteins.
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PMID:Inhibition of heat- and chemical-induced aggregation of various proteins reveals chaperone-like activity of the acute-phase component and serine protease inhibitor human alpha(1)-antitrypsin. 2011 85

Caloric restriction (CR) extends lifespan through a reduction in oxidative stress, delays the onset of morbidity and prolongs lifespan. We previously reported that long-term CR hastened clinical onset, disease progression and shortened lifespan, while transiently improving motor performance in G93A mice, a model of amyotrophic lateral sclerosis (ALS) that shows increased free radical production. To investigate the long-term CR-induced pathology in G93A mice, we assessed the mitochondrial bioenergetic efficiency and oxidative capacity (CS--citrate synthase content and activity, cytochrome c oxidase--COX activity and protein content of COX subunit-I and IV and UCP3-uncoupling protein 3), oxidative damage (MDA--malondialdehyde and PC--protein carbonyls), antioxidant enzyme capacity (Mn-SOD, Cu/Zn-SOD and catalase), inflammation (TNF-alpha), stress response (Hsp70) and markers of apoptosis (Bax, Bcl-2, caspase 9, cleaved caspase 9) in their skeletal muscle. At age 40 days, G93A mice were divided into two groups: Ad libitum (AL; n = 14; 7 females) or CR (n = 13; 6 females), with a diet equal to 60% of AL. COX/CS enzyme activity was lower in CR vs. AL male quadriceps (35%), despite a 2.3-fold higher COX-IV/CS protein content. UCP3 was higher in CR vs. AL females only. MnSOD and Cu/Zn-SOD were higher in CR vs. AL mice and CR vs. AL females. MDA was higher (83%) in CR vs. AL red gastrocnemius. Conversely, PC was lower in CR vs. AL red (62%) and white (30%) gastrocnemius. TNF-alpha was higher (52%) in CR vs. AL mice and Hsp70 was lower (62%) in CR vs. AL quadriceps. Bax was higher in CR vs. AL mice (41%) and CR vs. AL females (52%). Catalase, Bcl-2 and caspases did not differ. We conclude that CR increases lipid peroxidation, inflammation and apoptosis, while decreasing mitochondrial bioenergetic efficiency, protein oxidation and stress response in G93A mice.
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PMID:Caloric restriction shortens lifespan through an increase in lipid peroxidation, inflammation and apoptosis in the G93A mouse, an animal model of ALS. 2019 68


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