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:2.3.1.21 (CPT)
4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine kinase (AK) inhibitors potentiate the actions of endogenous adenosine (ADO) and ameliorate cerebral ischemic damage in animal models. The present study examined the effects of the AK inhibitor, 5-iodotubercidin (5-IT) in an in vitro model of neuronal ischemia, specifically, combined oxygen-glucose deprivation of rat cortical mixed neuronal-glial cultures. Oxygen-glucose deprivation caused extensive neuronal loss which was accompanied by a marked increase in ADO release into the extracellular medium, was ameliorated by exogenous ADO (10 microM(-1) mM), and was exacerbated by a high concentration of the selective A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 10 microM). 5-IT (1 microM) had no effect on extracellular ADO levels nor on neuronal loss. However, AK activity in these cultures was markedly suppressed during oxygen-glucose deprivation. Taken together, these data demonstrate a marked down-regulation of AK activity during oxygen-glucose deprivation in this in vitro model, providing an endogenous mechanism contributing to the accumulation of extracellular ADO, which exerts neuroprotective effects by activating the ADO A1 receptor.
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PMID:Inhibition of adenosine kinase during oxygen-glucose deprivation in rat cortical neuronal cultures. 973 97

The mechanism of action of the antiischemic effect of the antianginal agent trimetazidine remains uncertain. However, there is evidence that it inhibits long-chain fatty acid oxidation, which may increase the efficiency of myocardial oxygen utilization. We examined the effects of trimetazidine (0.1-5 mmol/L) on the activity of carnitine palmitoyltransferase-1 (CPT-1) in rat myocardium. Trimetazidine inhibited CPT-1 (IC50 1.3 mmol/L); this effect was less potent than that of perhexiline (IC50 77 mumol/L) or amiodarone (IC50 228 mumol/L), but appeared to interact with the enzyme at a similar site as that of both perhexiline and amiodarone. It is concluded that the relatively low potency of trimetazidine as a CPT-1 inhibitor makes this an unlikely mechanism to explain its therapeutic antiischemic effect.
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PMID:Effect of trimetazidine on carnitine palmitoyltransferase-1 in the rat heart. 982 81

We have investigated the effects of adenosine on the cardiovascular system of the Antarctic fish Pagothenia borchgrevinki. Continuous measurements of ventral and dorsal aortic blood pressures, heart rate (fh) and ventral aortic blood flow (cardiac output, q_dot ) were made using standard cannulation techniques and a single-crystal Doppler flowmeter. On line measurements of arterial P(O2) were made using an oxygen electrode connected to an extracorporeal loop. Adenosine (10 nmol kg(-)(1)) and the specific A(1)-receptor agonist N(6)-cyclopentyladenosine (CPA) elicited biphasic changes in the branchial and systemic resistances. While there was an initial decrease in the branchial resistance followed by an increase, the opposite was true for the systemic response. The resistance changes were significantly attenuated by aminophylline (a P(1)-receptor antagonist) and 8-cyclopentyltheophylline (CPT; an A(1)-receptor antagonist). In addition, adenosine induced an aminophylline-sensitive decrease in the arterial P(O2). The reduction was attenuated when pre-injection arterial P(O2) was low. Adenosine and CPA also caused a marked reduction in fh, with CPA being more potent. The bradycardia was blocked by aminophylline and CPT, demonstrating an involvement of A(1) receptors in this response.
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PMID:Cardiovascular responses to adenosine in the antarctic fish pagothenia borchgrevinki 1044 Oct 79

Under hypoxic conditions the atrial contents of long-chain acyl CoA (LCCoA) and long-chain acylcarnitine display a close correlation with the noxious effects of fasting on the atrial functions as well as with the amelioration effected by inhibitors of carnitine palmitoyltransferase I. These findings suggested that fatty acid oxidation was detrimental for the hypoxic atria. However, since changes of the LCCoA and LCCa levels which may occur together with the hypoxic disturbances attained under some other metabolic interventions had not been assessed yet, present investigation aimed to provide information about this issue. At the end of the prehypoxic equilibration period, all the treatments tested evoked a fall of the free-CoA levels whereas free-carnitine, LCCoA and LCCa remained unchanged. In the hypoxic atria, 4-pentenoate, an inhibitor of fatty acid beta-oxidation that also can be oxidized, did not change LCCoA and LCCa levels whereas the readily oxidizable pentanoate evoked a drop of LCCoA. These effects may be due to the trapping of CoA as the short-chain acyl esters of both substances. Since 4-pentenoate and pentanoate were noxious on the hypoxic atria even though they did not increase LCCoA and LCCa contents, it may be inferred that short-chain acyl esters might be deleterious during oxygen shortage. The exposure to 3-hydroxybutyrate, an oxidizable substrate whose availability increases during fasting, did not alter the LCCoA and LCCa contents, agreeing with the weak detrimental effects that it exerts on the hypoxic atria. On the other hand, insulin elicited a rise in the LCCoA and a fall in the LCCa contents. Inasmuch insulin had been shown to improve the performance of the hypoxic atria, these findings suggest that LCCoA might not be involved in the noxious effects of fatty acid oxidation whereas LCCa would be the major toxic catabolite.
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PMID:Effects of pentanoate, 4-pentenoate, 3-hydroxybutyrate and insulin on the tissue-levels of long-chain acyl CoA and acylcarnitine in the oxygenated and hypoxic rat atria. 1045 55

DNA topoisomerase (top) I inhibition activity of the natural alkaloid fagaronine (NSC157995) and its new synthetic derivative ethoxidine (12-ethoxy-benzo[c]phenanthridine) has been correlated with their molecular interactions and sequence specificity within the DNA complexes. Flow linear dichroism shows that ethoxidine exhibits the same inhibition of DNA relaxation as fagaronine at the 10-fold lower concentration. The patterns of DNA cleavage by top I show linear enhancement of CPT-dependent sites at the 0.016-50 microM concentrations of fagaronine, whereas ethoxidine suppress both top I-specific and CPT-dependent sites. Suppression of top I-mediated cleavage by ethoxidine is found to be specific for the sites, including strand cut between A and T. Fagaronine and ethoxidine are DNA major groove intercalators. Ethoxidine intercalates DNA in A-T sequences and its 12-ethoxy-moiety (absent in fagaronine) extends into the DNA minor groove. These findings may explain specificity of suppression by ethoxidine of the strong top I cleavage sites with the A(+1), T(-1) immediately adjacent to the strand cut. Fagaronine does not show any sequence specificity of DNA intercalation, but its highly electronegative oxygen of hydroxy group (absent in ethoxidine) is shown to be an acceptor of the hydrogen bond with the NH(2) group of G base of DNA. Ability of fagaronine to stabilize top I-mediated ternary complex is proposed to be determined by interaction of its hydroxy group with the guanine at position (+1) of the DNA cleavage site and of quaternary nitrogen interaction with top I. The model proposed provides a guidance for screening new top I-targeted drugs in terms of identification of molecular determinants responsible for their top I inhibition effects.
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PMID:Molecular determinants of site-specific inhibition of human DNA topoisomerase I by fagaronine and ethoxidine. Relation to DNA binding. 1065 45

During aerobic metabolism, a small amount of partially reduced oxygen is produced, yielding reactive oxygen species (ROS). Peroxisomes and mitochondria are major contributors to cellular ROS production, which is normally balanced by consumption by antioxidants. The fatty acid analogue tetradecylthioacetic acid (TTA) promotes mitochondrial and peroxisomal proliferation, and may induce oxidative stress and change the growth potential of cancer cells. In the present study, we found that TTA reduced [(3)H]thymidine incorporation in the glioma cell lines BT4Cn (rat), D54Mg (human), and GaMg (human) in a dose- and time-dependent manner. The 50% inhibitory TTA doses were approximately 125 microM for BT4Cn and D54Mg cells and 40 microM for GaMg cells after 4 days. alpha-Tochopherol counteracted this inhibition in GaMg cells. TTA enhanced the oxidation of [1-(14)C]palmitic acid, which could be explained by stimulation of enzymes involved in peroxisomal (fatty acyl-CoA oxidase) and/or mitochondrial (carnitine palmitoyltransferase) fatty acid oxidation. The glutathione content and the activities of glutathione peroxidase, glutathione reductase, and glutathione S-transferase were differentially affected. Increased malondialdehyde (MDA) production was seen in TTA-treated GaMg and D54Mg cells, but not in BT4Cn cells, in vitro. In BT4Cn tumor tissue from TTA-treated rats, MDA was increased while the alpha-tocopherol content tended to decrease. TTA increased the level of cytosolic cytochrome c in BT4Cn cells, which suggests induction of apoptotic cascades. Although several mechanisms are likely to be involved in the TTA-mediated effects on growth, we propose that modulation of cellular redox conditions caused by changes in fatty acid metabolism may be of vital importance.
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PMID:Growth reduction in glioma cells after treatment with tetradecylthioacetic acid: changes in fatty acid metabolism and oxidative status. 1126 48

Exposure of neonatal rat cardiac myocytes to palmitate and glucose produces apoptosis as seen by cytochrome c release, caspase 3-like activation, DNA laddering, and poly(ADP-ribose) polymerase cleavage. The purpose of this study was to understand the role of reactive oxygen species in the initiation of programmed cell death by palmitate. We found that palmitate (but not oleate) produces inhibition of carnitine palmitoyltransferase I, accumulation of ceramide, and inhibition of electron transport complex III. These events are subsequent to cytochrome c release and loss of the mitochondrial membrane potential. No differences in H2O2 production or N-terminal c-Jun kinase phosphorylation were detected between myocytes incubated in palmitate and control myocytes (nonapoptotic) incubated in oleate. These results suggest that the palmitate-induced loss of the mitochondrial membrane potential is not associated with H2O2 synthesis and that a membrane potential is required to generate reactive oxygen species following ceramide inhibition of complex III.
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PMID:Fatty acid-induced apoptosis in neonatal cardiomyocytes: redox signaling. 1129

Leptin, a circulating hormone secreted mainly from adipose tissues, is involved in the control of body weight. The plasma concentrations are correlated with body mass index, and are reported to be high in patients with insulin resistance, which is one of the major risk factors for cardiovascular disease. However, the direct effect of leptin on vascular wall cells is not fully understood. In this study, we investigated the effects of leptin on reactive oxygen species (ROS) generation and expression of monocyte chemoattractant protein-1 (MCP-1) in bovine aortic endothelial cells (BAEC). We found that leptin increases ROS generation in BAEC in a dose-dependent manner and that its effects are additive with those of glucose. Rotenone, thenoyltrifluoroacetone (TTFA), carbonyl cyanide m-chlorophenylhydrazone (CCCP), Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), uncoupling protein-1 (UCP1) HVJ-liposomes, or manganese superoxide dismutase (MnSOD) HVJ-liposomes completely prevented the effect of leptin, suggesting that ROS arise from mitochondrial electron transport. Leptin increased fatty acid oxidation by stimulating the activity of carnitine palmitoyltransferase-1 (CPT-1) and inhibiting that of acetyl-CoA carboxylase (ACC), pace-setting enzymes for fatty acid oxidation and synthesis, respectively. Leptin-induced ROS generation, CPT-1 activation, ACC inhibition, and MCP-1 overproduction were found to be completely prevented by either genistein, a tyrosine kinase inhibitor, H-89, a protein kinase A (PKA) inhibitor, or tetradecylglycidate, a CPT-1 inhibitor. Leptin activated PKA, and the effects of leptin were inhibited by the cAMP antagonist Rp-cAMPS. These results suggest that leptin induces ROS generation by increasing fatty acid oxidation via PKA activation, which may play an important role in the progression of atherosclerosis in insulin-resistant obese diabetic patients.
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PMID:Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. 1134 29

The purpose of this study was to investigate the possible effect of the trimetazidine derivative S-15176 on carnitine palmitoyltransferase1 (CPT-1) activity in rat heart and liver mitochondria. S-15176 was compared with the other antianginal agents amiodarone, perhexiline and trimetazidine, which do not show any hemodynamic effects and which are believed to exert their effects by switching the cellular metabolism towards glucose utilization at the expense of lipid metabolism, increasing the yield of oxygen utilization. S-15176 inhibited CPT-1 in vitro and was more effective in heart (IC(50)= 16.8 micro M) than in liver ( 50.8 +/- 3.0 micro M). In the heart, its was less effective than the physiological inhibitor malonyl-CoA (IC(50)= 2.1 micro M), but it was more potent than amiodarone (IC(50)= 140 micro M). Kinetic experiments demonstrated a non-competitive inhibition of CPT-1 by S-15176 indicating that the two compounds did not share the same site of action. CPT-1 inhibition was also obvious ex vivo, in heart and liver tissues, after a 2 week treatment with S-15176. This inhibitory effect may shift heart and liver metabolism from fatty acid to glucose oxidation and contribute to the anti-ischemic effects of the drug.
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PMID:Inhibition of mitochondrial carnitine palmitoyltransferase-1 by a trimetazidine derivative, S-15176. 1151 58

Several reports have shown that energy deprivation, as a result of hypoxia, hypoglycaemia or ischaemia, depresses excitatory synaptic transmission in virtually all brain areas. How this pathological condition affects inhibitory synaptic transmission is still unclear. In the present in vitro study, we coupled whole-cell patch clamp recordings from striatal neurones with focal stimulation of GABAergic nerve terminals in order to characterize the electrophysiological effects of combined oxygen and glucose deprivation (in vitro ischaemia) on inhibitory postsynaptic currents (IPSCs) in this brain area. We found that brief periods (2-5 min) of in vitro ischaemia invariably caused a marked depression of IPSC amplitude. This inhibitory effect was fully reversible on removal of the ischaemic challenge. It was coupled with an increased paired-pulse facilitation, suggesting the involvement of presynaptic mechanisms. Accordingly, the ischaemic inhibition of striatal GABAergic IPSCs was not caused by a shift in the reversal potential of GABA(A)-receptor mediated synaptic currents, and was independ- ent of postsynaptic ATP concentrations. Endogenous adenosine, acting on A1 receptors, appeared responsible for this presynaptic action as the ischaemic depression of IPSCs was prevented by CPT [8-(4-chlorophenylthio) adenosine] and DPCPX, two adenosine A1 receptor antagonists, and mimicked by the application of adenosine in the bathing solution. Conversely, ATP-sensitive potassium channels were not involved in the inhibition of IPSCs by ischaemia, as demonstrated by the fact that tolbutamide and glipizide, two blockers of these channels, were ineffective in preventing this electrophysiological effect. The early depression of GABA-mediated synaptic transmission might play a role in the development of irreversible neuronal injury in the course of brain ischaemia.
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PMID:Adenosine-mediated inhibition of striatal GABAergic synaptic transmission during in vitro ischaemia. 1152 87


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