Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Homocysteine (Hcy), an intermediate in methionine metabolism, has been proposed to be involved in hepatic fibrogenesis. Impaired liver function can alter Hcy metabolism. The aim of the present study was to determine plasma Hcy alterations in acute obstructive cholestasis and the subsequent biliary cirrhosis. Cholestasis was induced by bile duct ligation and sham-operated and unoperated rats were used as controls. The animals were studied on the days 7th, 14th, 21st and 28th after the operation. Plasma Hcy, cysteine, methionine, nitric oxide (NO) and liver S-adenosyl-methionine (SAM), S-adenosyl-homocysteine (SAH), SAM to SAH ratio and glutathione were measured. Chronic L-NAME treatment was also included in the study. Plasma Hcy concentrations were transiently elevated by the day 14th after bile duct ligation (P < 0.01) and subsequently returned to control levels. Similar relative fluctuations in plasma Hcy were observed in BDL rats after intraperitoneal methionine overload. Plasma methionine, cysteine and nitrite and nitrate were significantly increased after bile duct ligation. SAM to SAH ratio was diminished by the 1st week of cholestasis and remained significantly decreased throughout the study. These events were accompanied by a decrease in GSH to GSSG ratio in the liver. Chronic L-NAME treatment improved SAM to SAH ratio and prevented the elevation of plasma Hcy and methionine (P < 0.05) while couldn't influence the other parameters. In conclusion, this study demonstrates alterations in plasma Hcy and liver SAM and SAH contents in precirrhotic stages and in secondary biliary cirrhosis, for the first time. In addition, we observed that plasma Hcy concentrations in BDL rats follow a distinct pattern of alteration from what has been previously reported in other models of cirrhosis. NO overproduction may contribute to plasma Hcy elevation and liver SAM depletion after cholestasis.
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PMID:Homocysteine alterations in experimental cholestasis and its subsequent cirrhosis. 1576 80

Mitochondrial beta-ketothiolase and 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiencies are inherited neurometabolic disorders affecting isoleucine catabolism. Biochemically, beta-ketothiolase deficiency is characterized by intermittent ketoacidosis and urinary excretion of 2-methyl-acetoacetate (MAA), 2-methyl-3-hydroxybutyrate (MHB) and tiglylglycine (TG), whereas in MHBD deficiency only MHB and tiglylglycine accumulate. Lactic acid accumulation and excretion are also observed in these patients, being more pronounced in MHBD-deficient individuals, particularly during acute episodes of decompensation. Patients affected by MHBD deficiency usually manifest severe mental retardation and convulsions, whereas beta-ketothiolase-deficient patients present encephalopathic crises characterized by metabolic acidosis, vomiting and coma. Considering that the pathophysiological mechanisms responsible for the neurological alterations of these disorders are unknown and that lactic acidosis suggests an impairment of energy production, the objective of the present work was to investigate the in vitro effect of MAA and MHB, at concentrations varying from 0.01 to 1.0 mmol/L, on several parameters of energy metabolism in cerebral cortex from young rats. We observed that MAA markedly inhibited CO2 production from glucose, acetate and citrate at concentrations as low as 0.01 mmol/L. In addition, the activities of the respiratory chain complex II and succinate dehydrogenase were mildly inhibited by MAA. MHB, at 0.01 mmol/L and higher concentrations, strongly inhibited CO2 production from all tested substrates, as well as the respiratory chain complex IV activity. The other activities of the respiratory chain were not affected by these metabolites. The data indicate a marked blockage in the Krebs cycle and a mild inhibition of the respiratory chain caused by MAA and MHB. Furthermore, MHB inhibited total and mitochondrial creatine kinase activities, which was prevented by the use of the nitric-oxide synthase inhibitor L-NAME and glutathione (GSH). These data indicate that the effect of MHB on creatine kinase was probably mediated by oxidation or other modification of essential thiol groups of the enzyme by nitric oxide and other by-products derived from this organic acid. In contrast, MAA did not affect creatine kinase activity. Taken together, these observations indicate that aerobic energy metabolism is inhibited by MAA and to a greater extent by MHB, a fact that may be related to lactic acidaemia occurring in patients affected by MHBD and beta-ketothiolase deficiencies. If the in vitro effects detected in the present study also occur in vivo, it is tempting to speculate that they may contribute, at least in part, to the neurological dysfunction found in these disorders.
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PMID:Inhibition of energy metabolism by 2-methylacetoacetate and 2-methyl-3-hydroxybutyrate in cerebral cortex of developing rats. 1590 53

Depletion of glutathione (GSH), nitrosative stress and chronic intoxication with some neurotoxins have been postulated to play a major role in the pathogenesis of Parkinson's disease. This study aimed to examine the effects of acute and chronic treatments with 1,2,3,4-tetrahydroisoquinoline (TIQ), an endo-/exogenous substance suspected of producing Parkinsonism in human, on the levels of nitric oxide (NO), S-nitrosothiols and glutathione (GSH) in the whole rat brain and in its dopaminergic structures. TIQ administered at a dose of 50 mg/kg i.p. significantly increased the tissue concentrations of NO and GSH in the substantia nigra (SN), striatum (STR) and cortex (CTX) of rats receiving this compound both acutely and chronically. Moreover, it decreased the level of oxidized glutathione (GSSG) and enhanced GSH:GSSG ratio affecting in this way the redox state of brain cells. TIQ also increased the level of S-nitrosothiols when measured in the whole rat brain and CTX, although it markedly decreased their level in the STR after both treatments. Inhibition of the constitutive NO synthase by l-NAME in the presence of TIQ caused decreases in GSH and S-nitrosothiol levels in the brain. The latter effect shows that the TIQ-mediated increases in GSH and S-nitrosothiol concentrations were dependent on the enhanced NO level. The above-described results suggest that TIQ can act as a modulator of GSH, NO and S-nitrosothiol levels but not as a parkinsonism-inducing agent in the rat brain.
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PMID:Treatment with 1,2,3,4-tetrahydroisoquinolone affects the levels of nitric oxide, S-nitrosothiols, glutathione and the enzymatic activity of gamma-glutamyl transpeptidase in the dopaminergic structures of rat brain. 1594 55

Losartan, an angiotensin II type-1 receptor (AT1) antagonist, was used to investigate whether it can offer protection against the sustained hypertension, cardiac hypertrophy, and renal damage induced by chronic inhibition of nitric oxide (NO) by Nomega-nitro-L-arginine methyl ester (L-NAME). We studied the involvement of both NO metabolism and oxidative stress in L-NAME-induced hypertension, and how AT1 receptor antagonism may interact. Male Wistar albino rats were subjected to NO synthesis inhibition by the use of L-NAME (60 mg/kg/day), and the effects of losartan (10 mg/kg/day) in drinking water for six weeks were observed. After six weeks, animals were subjected to the measurements for systolic, mean, and diastolic blood pressure (BPs, BPm, and BPd, respectively). Under light ether anesthesia blood was withdrawn for ACE activity, NOx and creatinine determinations. Heart and kidneys were weighed, and organ indices were calculated comparing to their body weights. These tissues were immediately preserved for GSH, MDA, NOx estimations. Chronic L-NAME treatment raised BPs, BPm, and BPd, respectively, above the normal. Treatment also increased NOx in plasma, significantly decreased it in the heart, and tended to increase it in kidney. L-NAME caused GSH depletion in the heart and kidney tissues with a concomitant increase in MDA contents in both the tissues. Plasma creatinine doubled in L-NAME-treated animals. Plasma ACE activity showed a nonsignificant decrease below control. Concurrent treatment with losartan almost completely inhibited any rise in blood pressure. Losartan replenished the partly depleted cardiac and renal antioxidant GSH and ameliorated the increase of oxidative stress damage index, MDA. However, losartan alone did not change appreciably the plasma level or cardiac and renal contents of NO,. Losartan plus L-NAME treatment caused an increase in plasma ACE activity above control. Furthermore, losartan ameliorated the L-NAME induced increase in creatinine back to value nonsignificantly different from control.
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PMID:Effects of losartan on blood pressure, oxidative stress, and nitrate/nitrite levels in the nitric oxide deficient hypertensive rats. 1598 79

Despite the significant brain abnormalities, the neurotoxic mechanisms of brain injury in hypertryptophanemia are virtually unknown. In this work, it was investigated the in vitro effect of l-tryptophan on various parameters of oxidative stress, namely spontaneous chemiluminescence, thiobarbituric acid-reactive substances (TBA-RS), total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR) and glutathione (GSH) levels in cerebral cortex from 30-day-old rats. Tryptophan significantly increased chemiluminescence and TBA-RS measurements indicating that this amino acid induced lipid peroxidation in vitro. We also observed that tryptophan significantly decreased the brain antioxidant defenses by reducing the values of TRAP, TAR and GSH, reflecting that the overall content of antioxidants was reduced by tryptophan. Furthermore, the tryptophan-induced increase of TBA-RS was fully prevented by GSH and by combination of catalase plus superoxide dismutase, but not by the inhibitor of nitric oxide synthase N(omega)-nitro-L-arginine methyl ester (L-NAME). In case these findings also occur in human hypertryptophanemia or in other neurodegenerative diseases in which tryptophan accumulates, it is feasible that oxidative stress may be involved in the mechanism leading to the brain injury observed in patients affected by these disorders.
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PMID:Promotion of oxidative stress by L-tryptophan in cerebral cortex of rats. 1649 12

The role of mu3 opioid receptors in morphine-induced intraocular pressure (IOP) lowering effect and miosis was evaluated in conscious, dark-adapted New Zealand white (NZW) rabbits using a masked-design study. IOP and pupil diameter (PD) measurements were taken at just before and 0.5, 1, 2, 4, 6 h after monolateral instillation of morphine (10, 50 and 100 microg/30 microl) as compared to vehicle administered in the contralateral eye. Morphine-induced ocular effects were challenged by a pre-treatment with the non-selective opioid receptor antagonist, naloxone (100 microg/30 microl), the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME, 1%, 30 microl), or the non-selective mu3 opioid receptor inhibitor, reduced L-glutathione (GSH, 1%, 30 microl). Morphine induced a dose-dependent decrease in IOP and PD. Pre-treatment with naloxone totally prevented morphine-induced decrease in IOP and miosis. Ocular administration of L-NAME or GSH alone failed to affect IOP or PD of NZW rabbits. However, pre-treatment with either drugs significantly reduced, but not totally prevented ocular effects of morphine. These results suggest that biochemical mechanisms related to nitric oxide release are involved, at least in part, in morphine effects on the eye. Since the mu3 opioid receptor subtype is able to release nitric oxide and is sensitive to inactivation by GSH, it may be possible that mu3 opioid receptors are involved in morphine-induced miosis and reduction in IOP.
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PMID:Possible involvement of nitric oxide in morphine-induced miosis and reduction of intraocular pressure in rabbits. 1651 92

The present study was performed to evaluate the role of nitric oxide in the intraocular pressure (IOP) lowering effect and in the miotic action of morphine. The IOP was measured in conscious, normal, dark-adapted New Zealand white rabbits using a calibrated pneumatonometer. Experiments were conducted, in which rabbits' eyes were treated with morphine topically and unilaterally, while the fellow eyes received vehicle. IOP and pupil diameter (PD) measurements were taken 0.5 and 0 h before morphine administration and 0.5, 1, 2, 3, 4, and 5 h thereafter. The effects of a nonselective opioid receptor antagonist (naloxone), a nitric oxide synthase inhibitor (Nomega-nitro-L-arginine methyl ester; L-NAME), and a sulfhydryl reagent (reduced L-glutathione; GSH) on morphine-mediated changes in IOP and PD were also determined. Morphine (10, 33, and 100 microg) produced concentration-dependent decreases in IOP and reduced PD in both treated and untreated eyes of New Zealand white rabbits. IOP-lowering effect of morphine (100 microg) and reduction in PD were both significantly inhibited by pretreatment with naloxone (100 microg), L-NAME (0.5%), or GSH (100 microg). The results from this study indicate that morphine-induced ocular hypotension and reduction in PD are opioid-receptor-mediated responses that are associated with the release of nitric oxide. Because the mu3 opioid receptor subtype has a nitric-oxide-releasing activity and is sensitive to inactivation by GSH, it is concluded that morphine-induced ocular hypotension and miosis are mediated, in part, by activation of mu3 opioid receptors.
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PMID:Morphine-induced reduction of intraocular pressure and pupil diameter: role of nitric oxide. 1653 51

Grape seed proanthocyanidin extract (GPSE) at high doses has been shown to exhibit cytotoxicity that is associated with increased apoptotic cell death. Nitric oxide (NO), being a regulator of apoptosis, can be increased in production by the administration of GSPE. In a chick cardiomyocyte study, we demonstrated that high-dose (500 microg/ml) GSPE produces a significantly high level of NO that contributes to increased apoptotic cell death detected by propidium iodide and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. It is also associated with the depletion of intracellular glutathione (GSH), probably due to increased consumption by NO with the formation of S-nitrosoglutathione. Co-treatment with L-NAME, a NO synthase inhibitor, results in reduction of NO and apoptotic cell death. The decline in reduced GSH/oxidized GSH (GSSG) ratio is also reversed. N-Acetylcysteine, a thiol compound that reacts directly with NO, can reduce the increased NO generation and reverse the decreased GSH/GSSG ratio, thereby attenuating the cytotoxicity induced by high-dose GSPE. Taken together, these results suggest that endogenous NO synthase (NOS) activation and excessive NO production play a key role in the pathogenesis of high-dose GSPE-induced cytotoxicity.
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PMID:Cytotoxicity induced by grape seed proanthocyanidins: role of nitric oxide. 1655 1

Accumulation of the branched-chain alpha-keto acids (BCKA), alpha-ketoisocaproic acid (KIC), alpha-keto-beta-methylvaleric acid (KMV), and alpha-ketoisovaleric acid (KIV) and their respective branched-chain alpha-amino acids (BCAA) in tissues and biological fluids is the biochemical hallmark of patients affected by the neurometabolic disorder known as maple syrup urine disease (MSUD). Considering that brain energy metabolism is possibly altered in MSUD, the objective of this study was to determine creatine kinase (CK) activity, a key enzyme of energy homeostasis, in C6 glioma cells exposed to BCKA. The cells were incubated with 1, 5, or 10 mM BCKA for 3 h and the CK activity measured afterwards. The results indicated that the BCKA significantly inhibited CK activity at all tested concentrations. Furthermore, the inhibition caused by the BCKA on CK activity was totally prevented by preincubation with the energetic substrate creatine and by coincubation with the N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, indicating that deficit of energy and nitric oxide (NO) are involved in these effects. In contrast, other antioxidants such as glutathione (GSH) and trolox (soluble Vitamin E) were not able to prevent CK inhibition. In addition, we observed that the C6 cells changed their usual rounded morphology when exposed for 3 h to 10 mM BCKA and that creatine and L-NAME prevented these morphological alterations. Considering the importance of CK for brain metabolism homeostasis, it is conceivable that inhibition of this enzyme by increased levels of BCKA may contribute to the neurodegeneration of MSUD patients.
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PMID:Creatine and antioxidant treatment prevent the inhibition of creatine kinase activity and the morphological alterations of C6 glioma cells induced by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. 1663 2

Maple syrup urine disease (MSUD) is an inherited neurometabolic disorder biochemically characterized by the accumulation of the branched-chain alpha-keto acids (BCKA) alpha-ketoisocaproic (KIC), alpha-keto-beta-methylvaleric (KMV) and alpha-ketoisovaleric (KIV) and their respective branched-chain alpha-amino acids in body fluids and tissues. Affected MSUD patients have predominantly neurological features, including cerebral edema and atrophy whose pathophysiology is not well established. In the present study we investigated the effects of KIC, KMV and KIV on cell morphology, cytoskeleton reorganization, actin immunocontent and on various parameters of oxidative stress, namely total antioxidant reactivity (TAR), glutathione (GSH) and nitric oxide concentrations, and on the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) in C6 glioma cells. We initially observed that C6 cultivated cells exposed for 3 h to the BCKA (1 and 10 mM) changed their usual rounded morphology to a fusiform or process-bearing cell appearance, while 24 h exposure to these organic acids elicited massive cell death. Rhodamine-labelled phalloidin analysis revealed that these organic acids induced reorganization of the actin cytoskeleton with no modifications on total actin content. It was also observed that 3h cell exposure to low doses of all BCKA (1 mM) resulted in a marked reduction of the non-enzymatic antioxidant defenses, as determined by TAR and GSH measurements. In addition, KIC provoked a reduced activity of SOD and GPx, whereas KMV caused a diminution of SOD activity. In contrast, CAT activity was not modified by the metabolites. Furthermore, nitric oxide production was significantly increased by all BCKA. Finally, we observed that the morphological features caused by BCKA on C6 cells were prevented by the use of the antioxidants GSH (1.0 mM), alpha-tocopherol (trolox; 10 microM) and Nomega-nitro-L-arginine methyl ester (L-NAME; 500 microM). These results strongly indicate that oxidative stress might be involved in the cell morphological alterations and death, as well as in the cytoskeletal reorganization elicited by the BCKA. It is presumed that these findings are possibly implicated in the neuropathological features observed in patients affected by MSUD.
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PMID:Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. 1682 90


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