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)

To determine whether nitric oxide (NO)/peroxynitrite plays any role in neurodestruction observed in ischemic cochlea of the guinea pig, the effects of NO donors like S-nitrosocysteine (S-NC) and nitroglycerin (NTG), peroxynitrite generators like 3-morpholinosydnonimine (SIN-1), peroxynitrite inhibitors like superoxide dismutase plus catalase (SOD/Cat), as well as NOS inhibitors like N(G)-nitro-l-arginine methyl ether (L-NAME), were tested on normal and ischemic cochleae. Various concentrations of S-NC and SIN-1 were introduced into the perilymphatic space of normal guinea pig cochlea. Quantitative scanning electron microscopy of inner and outer hair cells was carried out 2 days later. To determine the level of NO in the cochlea after 20 to 120 min of ischemia, nitrites/nitrates in the perilymph were measured. The effects of NO on the ischemic cochlea were tested by infusion of SOD/Cat, L-NAME, S-NC, and NTG into the perilymphatic space just before decapitation. Introduction of fixative into the cochlea was delayed for 15 min to investigate the effects of the chemicals on nerve endings at the base of inner hair cells. The results showed that the level of nitrites/nitrates tended to decline with increasing time of ischemia. There was no significant hair cell loss in the cochleae treated with SIN-1 or S-NC. At 15 min after ischemia, most of the nerve endings at the base of the inner hair cells were protected from damage when 1 mM S-NC or NTG was infused into the perilymph. Taken together, the results indicate that NO/peroxynitrite is unlikely to be involved in the neurodestruction in the ischemic cochlea. In fact, exogenous NO may have a neural protective effect.
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PMID:Effects of nitric oxide on normal and ischemic cochlea of the guinea pig. 1131 72

To study the relationship of oxidative, antioxidative constituents and antioxidases in blood with chronic cholecystitis containing gallstone, levels of lipoperoxides (LPO), nitric oxide (NO), vitamin C(VC), vitamin E (VE) and beta-carotene (beta-CAR) in plasma as well as level of LPO, activities of superoxide dismulase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in erythrocytes were investigated by spectrophotometric assay in 107 patients with this condition (PCg) and 100 healthy volunteers (HVs). Compared with HVs group, the average value of LPO and NO in plasma and that of LPO in erythrocytes of PCg group were significantly increased (P < 0.0001), while that of VC, VE and beta-CAR in plasma and the average activities of SOD, CAT and GSH-Px in erythrocytes were significantly decreased (P < 0.0001). Linear regression and correlation analysis for 107 preoperative PCg showed that the value of LPO and NO in plasma and that of LPO in erythrocytes of PCg gradually increased (P < 0.0001), representing a significant linear positive correlation. The value of VC, VE and beta-CAR in plasma and that of SOD, CAT and GSH-Px in erythrocytes of PCg gradually decreased (P < 0.0001), representing a significant linear negative correlation. Stepwise regression and correlation analysis for 107 preoperative PCg suggested that the closest correlation was observed between the course of disease and the value of NO and VC in plasma and that of SOD, GSH-Px and LPO in erythrocytes, r = 0.7306, F = 32.1408, P < 0.0001. Compared with the preoperative PCg group, the average value of LPO and NO in plasma and that of LPO in erythrocytes of the postoperative PCg group were significantly decreased (P < 0.0001). Furthermore, the average value of VC in plasma and that of SOD, CAT and GSH-Px in erythrocytes of the postoperative PCg group were significantly increased (P < 0.0001), whereas no significant difference was found between their average value of VE and beta-CAR in plasma. These findings suggested that oxidative stress was an aggravating pathological condition in PCg group. Therefore, we recommend that in treating PCg, antioxidants such as VC, VE, beta-CAR should be given in order to alleviate their potential oxidative damages.
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PMID:Oxidative stress before and after operation in patients with chronic cholecystitis containing gallstone. 1135 58

Neuronal damage in glutaryl-CoA dehydrogenase deficiency (GDD) has previously been addressed to N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity of the accumulating neurotoxic metabolite 3-hydroxyglutarate. However, acute encephalopathic crises in GDD patients are typically precipitated by febrile illness or even routine vaccinations, suggesting a potentiating role of inflammatory cytokines. In the present study we investigated the effect of interleukin-1beta and interferon-gamma on 3-hydroxyglutarate toxicity in rat cortical astrocyte cultures and neonatal rat hippocampal cultures. A cotreatment of both culture systems with interleukin-1beta and interferon-gamma induced the protein expression of astrocytic inducible nitric oxide synthase (iNOS), resulting in increased nitric oxide (NO) production. Cytokine pretreatment alone had no effect on cell viability but potentiated 3-hydroxyglutarate neurotoxicity. NOS inhibition by aminoguanidine and L-NAME prevented an iNOS-mediated potentiation of 3-hydroxyglutarate neurotoxicity but failed to protect neurons against 3-hydroxyglutarate alone. In contrast, superoxide dismutase/catalase as well as MK-801 prevented toxicity of 3-hydroxyglutarate alone as well as its potentiation by iNOS, supporting a central role of NMDA receptor stimulation with subsequently increased superoxide anion production. It is concluded that the potentiation of 3-hydroxyglutarate neurotoxicity is most probably due to an induction of astrocytic iNOS and concomitantly increased NO production, enabling enhanced peroxynitrite formation. Thus, we provide evidence for a neuroimmunological approach to the precipitation of acute encephalopathic crises in GDD by inflammatory cytokines.
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PMID:Potentiation of 3-hydroxyglutarate neurotoxicity following induction of astrocytic iNOS in neonatal rat hippocampal cultures. 1142 52

Oxygen radicals are considered as an important regulator in the pathogenesis of Helicobacter pylori (H. pylori)-induced gastric ulceration and carcinogenesis. Inflammatory genes including inducible nitric oxide synthase (iNOS) may be regulated by oxidant-sensitive transcription factor, nuclear factor-kappaB (NF-kappaB). iNOS induction has been related to gastric apoptosis. We studied the role of NF-kappaB on iNOS expression and apoptosis in H. pylori-stimulated gastric epithelial AGS cells. AGS cells were treated with antisense oligonucleotide (AS ODN) for NF-kappaB subunit p50, an antioxidant enzyme catalase, an inhibitor of NF-kappaB activation pyrrolidine dithiocarbamate (PDTC), iNOS inhibitors N(G)-nitro-L-arginine-methyl ester (L-NAME) and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), a peroxynitrite donor SIN-1, and a nitric oxide donor NOC-18 in the presence or absence of H. pylori. H. pylori induced cytotocixity time- and dose-dependently, which occurred with induction in iNOS expression and nitrite production. SIN-1 and NOC-18 induced dose-dependent cytotoxicity in AGS cells. Catalase, PDTC, L-NAME, and AMT prevented H. pylori-induced cytotoxicity and apoptosis. It was related to their inhibition on iNOS expression and nitrite production. The cells treated with AS ODN had low levels of p50 and NF-kappaB and inhibited H. pylori-induced cytotoxicity, apoptosis, iNOS expression, and nitrite production. In conclusion, NF-kappaB plays a novel role in iNOS expression and apoptosis in H. pylori-infected gastric epithelial cells.
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PMID:NF-kappaB, inducible nitric oxide synthase and apoptosis by Helicobacter pylori infection. 1146 73

Patients on hemodialysis are prone to infection. Neutrophils are the host's first line of defense against certain invading pathogenic microorganisms. Since apoptotic neutrophils are functionally compromised we examined the effect of dialysis membranes on neutrophil apoptosis. Dialysis patients showed greater (p < 0.001) neutrophil apoptosis when compared with control subjects. Cellulose acetate membranes directly promoted (p < 0.001) neutrophil apoptosis. Cellulose acetate membrane-treated neutrophils exhibited greater apoptosis (p < 0.01) when compared with polysulfone membrane-treated neutrophils. Superoxide dismutase (SOD) partly inhibited the cellulose acetate membrane-induced neutrophil apoptosis, whereas both catalase and dimethylthiourea (DMTU) inhibited the polysulfone membrane-induced neutrophil apoptosis. Similarly, L-NAME, a nitric oxide synthase inhibitor, attenuated both the cellulose acetate and the polysulfone membrane-induced neutrophil apoptosis. In addition, cellulose acetate and monocyte interaction products promoted (p < 0.001) neutrophil apoptosis. These results suggest that dialysis membranes can promote neutrophil apoptosis directly as well as through their interaction with monocytes. The direct effect of dialysis membranes seems to be mediated partly through the generation of reactive oxygen species.
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PMID:Dialysis membrane-induced neutrophil apoptosis is mediated through free radicals. 1149 59

In strains of the snail Biomphalaria glabrata (Gastropoda) that are resistant to the parasite Schistosoma mansoni (Trematoda), hemocytes in the hemolymph are responsible for elimination of S. mansoni sporocysts. The defensive role of reactive nitrogen species was investigated in in vitro interactions between hemocytes derived from the resistant 13-16-R1 strain of B. glabrata and the parasite. The nitric oxide synthase (NOS) inhibitor N(omega)-nitro-L-arginine methylester (L-NAME) and the nitric oxide (NO) scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide reduced cell-mediated killing of S. mansoni sporocysts. To determine if peroxynitrite (ONOO-) is involved in killing, assays were run in the presence of the ONOO- scavengers uric acid and deferoxamine. These did not influence the rate of parasite killing, indicating that NO is directly responsible for mediating cytotoxicity, but ONOO- is not. The combination of the NOS inhibitor L-NAME and catalase, an enzyme that detoxifies hydrogen peroxide (H2O2), reduced average sporocyst mortality to a greater extent than L-NAME alone. Killing of the sporocysts was, however, not totally inhibited. It is suggested that NO and H2O2 are both involved in hemocyte-mediated toxicity of 13-16-R1 B. glabrata against S. mansoni sporocysts.
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PMID:Involvement of nitric oxide in killing of Schistosoma mansoni sporocysts by hemocytes from resistant Biomphalaria glabrata. 1153 41

In evaluating mechanisms of trimethyltin (TMT)-initiated neuronal damage, the present study focused on involvement of reactive oxygen species, protein kinase C (PKC), and glutamate receptors. Exposure of cerebellar granule cells to TMT (0.01-0.1 microM) produced primarily apoptosis, but higher concentrations were associated with cellular lactate dehydrogenase efflux and necrosis. TMT increased generation of cellular reactive oxygen species, which was inhibited by either L-NAME (inhibitor of nitric oxide synthase, NOS) or catalase, indicating that both NO and H(2)O(2) are formed on TMT exposure. Since chelerythrine (selective PKC inhibitor) also inhibited oxidative species generation, PKC appears to play a significant role in TMT-induced oxidative stress. The metabotropic glutamate receptor antagonist, MCPG, (but not MK-801) prevented oxidative species generation, indicating significant involvement of metabotropic receptors (but not NMDA receptors) in TMT-induced oxidative stress. NOS involvement in the action of TMT was confirmed through measurement of nitrite, which increased concentration dependently. Nitrite accumulation was blocked by L-NAME, chelerythrine, or MCPG, showing that NO is generated by TMT and that associated changes in NOS are regulated by a PKC-mediated mechanism. Oxidative damage by TMT was demonstrated by detection of elevated malondialdehyde levels. It was concluded that low concentrations of TMT (0.01-0.1 microM) cause apoptotic cell death in which oxidative signaling is an important event. Higher concentrations of TMT initiate necrotic death, which involves both an oxidative and a non-oxidative component. TMT-induced necrosis but not apoptosis in granule cells is mediated by glutamate receptors.
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PMID:Mechanisms of the apoptotic and necrotic actions of trimethyltin in cerebellar granule cells. 1160 4

Vascular endothelial growth factor (VEGF) is a potent vascular endothelial cell-specific mitogen that modulates endothelial cell function. In the present study, we show that VEGF induces manganese-superoxide dismutase (MnSOD) mRNA and protein in human coronary artery endothelial cells (HCAEC) and pulmonary artery endothelial cells. VEGF-mediated induction of MnSOD mRNA was inhibited by pretreatment with the NADPH oxidase inhibitors, diphenyleneiodonium (DPI), and 4-(2-aminoethyl)-benzenesulfonyl fluoride, but not with the nitric oxide synthase inhibitor L-NAME (N-monomethyl-L-arginine) or the xanthine oxidase inhibitor allopurinol. VEGF stimulation of MnSOD was also inhibited by adenoviral-mediated overexpression of catalase Cu, Zn-SOD and a dominant-negative form of the small GTPase component of NADPH oxidase Rac1 (Rac1N17). Treatment of HCAEC with VEGF resulted in a transient increase in ROS production at 20 min, as measured by 2,7-dichlorodihydrofluorescein oxidation. This effect was abrogated by expression of Rac1N17. Taken together, these findings suggest that VEGF induces MnSOD by an NADPH oxidase-dependent mechanism and that VEGF signaling in the endothelium is coupled to the redox state of the cell.
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PMID:Vascular endothelial growth factor induces manganese-superoxide dismutase expression in endothelial cells by a Rac1-regulated NADPH oxidase-dependent mechanism. 1164 Dec 65

1. Disruption of calcium homeostasis during neurodegenerative diseases is known to trigger apoptotic or necrotic death in neuronal cells. Recently, the authors reported that intracellular calcium restriction by NMDA receptor antagonists induces apoptosis in cortical cultures. To evaluate whether further restriction of intracellular free calcium can induce apoptosis or necrosis, we examined the neurotoxic characterization of BAPTA/AM, a permeable free calcium chelator, in mouse cortical cultures. 2. Exposure of mixed (glia and neuron) cortical cultures (DIV 13-16) to 3-10 microM BAPTA/AM (non-toxic concentration for glial cells) for 24-48 hr resulted in delayed and necrotic neuronal death. The necrotic findings included swelling and loss of mitochondria and endoplasmic reticulum (ER) with neuronal membrane rupture 24 hr after treatment with BAPTA/AM. Simultaneously, we observed a few TUNEL-positive cells in the neuronal subpopulation of the same cultures. 3. The neurotoxicity evoked by BAPTA/AM (10 microM) was significantly attenuated by the addition of 0.5 microM cycloheximide (a protein synthesis inhibitor), 10 microM actinomycin D (an RNA transcription inhibitor), a high extracellular potassium concentration (total 15 mM KCl), 100 microM t-ACPD (a metabotrophic agonist), 100 microM alpha-tocopherol (a free radical scavenger), 100 microM deferoxamine (a ferric ion chelator), 100 microM L-NAME (a nitric oxide synthase (NOS) inhibitor), 50 microM DNQX (a non-NMDA receptor blocker), and 3-30 microM esculetin (a lipoxygenase inhibitor). However, 0.3-3 mM ASA (a cyclooxygenase inhibitor), 100 ng/ml nerve growth factor (NGF), 10 microM MK-801 (a NMDA receptor antagonist), 20 microM zVAD-fmk (caspase inhibitor) and 50 U/ml catalase failed to inhibit the injury. 4. However, NGF and catalase blocked the neurotoxicity induced by BAPTA/AM in young neuronal cells (DIV 6). BAPTA/AM (10 microM) did not alter the expression of inducible nitric oxide synthase (iNOS) on glial cells. 5. These results suggest that the feature of neuronal death induced by BAPTA/AM exhibits predominantly delayed necrosis mediated by lipoxygenase-dependent free radicals.
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PMID:BAPTA/AM, an intracellular calcium chelator, induces delayed necrosis by lipoxygenase-mediated free radicals in mouse cortical cultures. 1164 60

Pyridostigmine bromide (PB) is a reversible cholinesterase inhibitor used for treatment of myasthenia gravis and for prophylactic protection against organophosphate nerve agent. We previously showed PB can induce apoptotic death in rat brain following systemic treatment. To study mechanisms by which PB induces brain cell death, cultured rat cerebellar granule cells were used. Cytotoxicity was determined after exposure to PB (10-1000 microM) for 24 h; a high concentration of PB (>500 microM) significantly increased lactate dehydrogenase release, which was reduced by pretreatment with the antioxidant, N-t-butyl-alpha-phenyl-nitrone (PBN). Apoptosis, as determined by TUNEL staining, was concentration dependent (10-250 microM) after a 24-h exposure and cytotoxicity was confirmed by gel electrophoresis of DNA, release of cytochrome c from mitochondria, elevation of caspase activity, and electron microscopy. The oxidant-sensitive fluorescent dye 2',7'-dichlorofluorescin diacetate was used to detect reactive oxidative species (ROS) generation. Pretreatment with PBN, superoxide dismutase, catalase, or the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) blocked PB-induced ROS generation and apoptotic cell death. Pretreatment with atropine or MK-801 blocked ROS generation and the subsequent neurotoxicity, showing that both muscarinic and NMDA receptors mediate the response. DNA extracted from PB-treated cells revealed oligonucleosomal fragmentation on gel electrophoresis and antioxidants attenuated the DNA fragmentation, providing further evidence for a link of ROS generation and apoptosis. These results indicate that muscarinic receptor-mediated ROS generation is an initiating factor in PB-induced apoptotic cell death and activation of the NMDA glutamate receptor is directly linked to the response.
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PMID:Reactive oxygen species mediate pyridostigmine-induced neuronal apoptosis: involvement of muscarinic and NMDA receptors. 1170 96


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