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)

The aim of this study was to test the effect of L: -arginine methyl ester (L-Arg) on indices of free radical involvement in a rat model of experimental nephrocalcinosis. Twenty-eight Sprague-Dawley rats were randomized into four groups of seven. The first group (G1), the sham-control group received pure distilled drinking water. The second group (G2) received drinking water containing 0.7% ethylene glycol (EG) in distilled water for 3 weeks. The third group (G3) received drinking water containing 0.7% EG in distilled water for 3 weeks and L-Arg was administered for 3 weeks. The fourth group (G4) received drinking water containing 0.7% EG in distilled water for 3 weeks and L-NAME was administered for 3 weeks. Urine and aortic blood was collected to determine some parameters. The kidneys were also removed for histological examination. The increase in blood urea nitrogen, serum creatinine, K(+), Mg(2+ )and uric acid were mild in group 3 compared with the groups 2 and 4. The urinary concentrations of Na(+), K(+), Mg(2+) and uric acid were noticed to be similar among the groups. However, Ca(2+ )and oxalate excretion were significantly higher in groups 2, 3 and 4 than in group 1. The mean values of SOD, CAT and GSH-Px values were significantly increased in group 3 when compared to groups 2 and 4. Presence of aggregated urinary crystals was clearer in experimental groups compared to group 1. The tubular dilatation, epithelial degeneration and lymphocytic infiltration were significantly found in groups 2 and 4. Mild tissue damage was observed in L-Arg-pretreated rats. Under polarized light microscope intense crystals in the cortex and medulla were observed in the kidney of group 2 and 4 and moderate crystals were noticed in group 3. In conclusion, L-Arg supplementation may decrease free radicals and tubulary membrane injury in nephrocalcinosis due to infiltrating leukocytes and decreased antioxidant enzyme activities in rats fed with EG diet.
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PMID:The effect of L-arginine methyl ester on indices of free radical involvement in a rat model of experimental nephrocalcinosis. 1682 49

There is evidence that nitric oxide (NO), superoxide (O(2)(*-)), and their associated reactive nitrogen species (RNS) produced by vascular endothelial cells (ECs) in response to hemodynamic forces play a role in cell signaling. NO is known to impair mitochondrial respiration. We sought to determine whether exposure of human umbilical vein ECs (HUVECs) to steady laminar shear stress and the resultant NO production modulate electron transport chain (ETC) enzymatic activities. The activities of respiratory complexes I, II/III, and IV were dependent on the presence of serum and growth factor supplement in the medium. EC exposure to steady laminar shear stress (10 dyn/cm(2)) resulted in a gradual inhibition of each of the complexes starting as early as 5 min from the flow onset and lasting up to 16 h. Ramp flow resulted in inhibition of the complexes similar to that of step flow. When ECs were sheared in the presence of the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 100 microM), the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO; 100 microM), or the peroxynitrite (ONOO(-)) scavenger uric acid (UA; 50 microM), the flow-inhibitory effect on mitochondrial complexes was attenuated. In particular, L-NAME and UA abolished the flow effect on complex IV. Increased tyrosine nitration was observed in the mitochondria of sheared ECs, and UA blocked the shear-induced nitrotyrosine staining. In summary, shear stress induces mitochondrial RNS formation that inhibits the electron flux of the ETC at multiple sites. This may be a critical mechanism by which shear stress modulates EC signaling and function.
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PMID:Shear-induced reactive nitrogen species inhibit mitochondrial respiratory complex activities in cultured vascular endothelial cells. 1702 Sep 31

Labrador tea (Ledum groenlandicum Retzius) is an ericaceae widely distributed in North America. The leaves and twigs were used in Native American traditional medicine to treat several inflammatory pathologies such as asthma, rheumatisms and burns. Reactive oxygen species as well as reactive nitrogen species such as nitric oxide (NO) contribute significantly to these pathologies. In this study, the antioxidant, anti-inflammatory and anticancer activities of crude methanol extracts of leaves and twigs from Ledum groenlandicum were investigated. Both extracts showed a strong antioxidant activity using the ORAC method and a cell based-assay. Moreover, the twig and leaf extracts showed significant anti-inflammatory activity, inhibiting NO release, respectively, by 28 and 17% at 25 microg/ml in LPS-stimulated RAW 264.7 macrophages. In comparison, N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, reduced NO release by 24% at 25 microg/ml. The twig extract was also found to be active against DLD-1 colon carcinoma and A-549 lung carcinoma cells, with IC(50) values of 43+/-1 and 65+/-8 microg/ml, respectively. The bioguided study of the twig extract resulted in the isolation and identification of ursolic acid, a known triterpene. Ursolic acid was active against DLD-1 (IC(50): 9.3+/-0.3 microM) and A-549 (IC(50): 8.9+/-0.2 microM), suggesting it is, in part, responsible of the anticancer activity of the twig extract.
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PMID:Antioxidant, anti-inflammatory and anticancer activities of methanolic extracts from Ledum groenlandicum Retzius. 1715 57

Nitrogen Dioxide (NO2) is a product of high-temperature combustion and an environmental oxidant of concern. We have recently reported that early changes in NO2-exposed human bronchial epithelial cells are causally linked to increased generation of proinflammatory mediators, such as nitric oxide/nitrite and cytokines like interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-8. The objective of the present in vitro study was to further delineate the cellular mechanisms of NO2-mediated toxicity, and to define the nature of cell death that ensues upon exposure of normal human bronchial epithelial (NHBE) cells to a brief high dose of NO2. Our results demonstrate that the NHBE cells undergo apoptotic cell death during the early post-NO2 period, but this is independent of any significant increase in caspase-3 activity. However, necrotic cell death was more prevalent at later time intervals. Interestingly, an increased expression of HO-1, a redox-sensitive stress protein, was observed in NO2-exposed NHBE cells at 24 h. Since neutrophils (PMNs) play an active role in acute lung inflammation and resultant oxidative injury, we also investigated changes in human PMN-NHBE cell interactions. As compared to normal cells, increased adhesion of PMNs to NO2-exposed cells was observed, which resulted in an increased NHBE cell death. The latter was also increased in the presence of IL-8 and TNF-alpha + interferon (IFN)-gamma, which correlated with upregulation of intercellular adhesion molecule-1 (ICAM-1). Our results confirmed an involvement of nitric oxide (NO) in NO2-induced cytotoxicity. By using NO synthase inhibitors such as L-NAME and 3-aminoguanidine (AG), a significant decrease in cell death, PMN adhesion, and ICAM-1 expression was observed. These findings indicate a role for the L-arginine/NO synthase pathway in the observed NO2-mediated toxicity in NHBE cells. Therapeutic strategies aimed at controlling excess generation of NO and/or inflammatory cytokines may be useful in alleviating NO2-mediated adverse effects on the bronchial epithelium.
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PMID:Effects of nitrogen dioxide on the expression of intercellular adhesion molecule-1, neutrophil adhesion, and cytotoxicity: studies in human bronchial epithelial cells. 1716 65

Quinolinic acid (QA) is an endogenous excitotoxin acting on N-methyl-d-aspartate receptors (NMDARs) that leads to the pathologic and neurochemical features similar to those observed in Huntington's disease (HD). The mechanism of QA toxicity also involves free radicals formation and oxidative stress. NMDARs are particularly vulnerable to the action of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that can act as modulators of the activity of protein tyrosine kinases (PTKs) and phosphotyrosine phosphatases (PTPs). Because QA is able to activate neuronal nitric oxide synthase (nNOS) as well as to stimulate the NMDARs, we evaluated the effect of Nomega-Nitro-l-arginine-methyl ester (l-NAME), a selective nNOS inhibitor, on QA-induced neurotoxicity in rat corticostriatal slices. In electrophysiologic experiments we observed that slice perfusion with QA induced a strong reduction of field potential (FP) amplitude, followed by a partial recovery at the end of the QA washout. In the presence of l-NAME the recovery of FP amplitude was significantly increased with respect to QA alone. In synaptosomes, prepared from corticostriatal slices after the electrophysiologic recordings, we observed that l-NAME pre-incubation reversed the QA-mediated inhibitory effects on protein tyrosine phosphorylation pattern, c-src, lyn, and fyn kinase activities and tyrosine phosphorylation of NMDAR subunit NR2B, whereas the PTP activity was not recovered in the presence of l-NAME. These findings suggest that NO plays a key role in the molecular mechanisms of QA-mediated excitotoxicity in experimental model of HD.
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PMID:L-NAME reverses quinolinic acid-induced toxicity in rat corticostriatal slices: Involvement of src family kinases. 1726 64

We have shown that cold perfusion of hearts generates reactive oxygen and nitrogen species (ROS/RNS). In this study, we determined 1) whether ROS scavenging only during cold perfusion before global ischemia improves mitochondrial and myocardial function, and 2) which ROS leads to compromised cardiac function during ischemia and reperfusion (I/R) injury. Using fluorescence spectrophotometry, we monitored redox balance (NADH and FAD), O(2)(*-) levels and mitochondrial Ca(2+) (m[Ca(2+)]) at the left ventricular wall in 120 guinea pig isolated hearts divided into control (Con), MnTBAP (a superoxide dismutase 2 mimetic), MnTBAP (M) + catalase (C) + glutathione (G) (MCG), C+G (CG), and N(G)-nitro-L-arginine methyl ester (L-NAME; a nitric oxide synthase inhibitor) groups. After an initial period of warm perfusion, hearts were treated with drugs before and after at 27 degrees C. Drugs were washed out before 2 h at 27 degrees C ischemia and 2 h at 37 degrees C reperfusion. We found that on reperfusion the MnTBAP group had the worst functional recovery and largest infarction with the highest m[Ca(2+)], most oxidized redox state and increased ROS levels. The MCG group had the best recovery, the smallest infarction, the lowest ROS level, the lowest m[Ca(2+)], and the most reduced redox state. CG and L-NAME groups gave results intermediate to those of the MnTBAP and MCG groups. Our results indicate that the scavenging of cold-induced O(2)(*-) species to less toxic downstream products additionally protects during and after cold I/R by preserving mitochondrial function. Because MnTBAP treatment showed the worst functional return along with poor preservation of mitochondrial bioenergetics, accumulation of H(2)O(2) and/or hydroxyl radicals during cold perfusion may be involved in compromised function during subsequent cold I/R injury.
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PMID:ROS scavenging before 27 degrees C ischemia protects hearts and reduces mitochondrial ROS, Ca2+ overload, and changes in redox state. 1728 67

Nitric oxide (NO) is thought to play multiple roles in skeletal muscle including regulation of some adaptations to contractile activity, but appropriate methods for the analysis of intracellular NO activity are lacking. In this study we have examined the intracellular generation of NO in isolated single mature mouse skeletal muscle fibres at rest and following a period of contractile activity. Muscle fibres were isolated from the flexor digitorum brevis muscle of mice and intracellular NO production was visualized in real-time using the fluorescent NO probe 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM DA). Some leakage of DAF-FM was apparent from fibres loaded with the probe, but they retained sufficient probe to respond to changes in intracellular NO following addition of the NO donor 3-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-propanamine (NOC-7) up to 30 min after loading. Electrically stimulated contractions in isolated fibres increased the rate of change in DAF-FM fluorescence by approximately 48% compared to non-stimulated fibres (P < 0.05) and the rate of change in DAF-FM fluorescence in the stimulated fibres returned to control values by 5 min after contractions. Treatment of isolated fibres with the NO synthase inhibitors NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) or NG-monomethyl-L-arginine (L-NMMA) reduced the increase in DAF-FM fluorescence observed in response to contractions of untreated fibres. Treatment of fibres with the cell-permeable superoxide scavenger 4,5-dihydroxy-1,3-benzenedisulphonic acid (Tiron) also reduced the increase in fluorescence observed during contractions suggesting that superoxide, or more probably peroxynitrite, contributes to the fluorescence observed. Thus this technique can be used to examine NO generation in quiescent and contracting skeletal muscle fibres in real time, although peroxynitrite and other reactive nitrogen species may potentially contribute to the fluorescence values observed.
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PMID:Real-time measurement of nitric oxide in single mature mouse skeletal muscle fibres during contractions. 1733 97

Lenses from mice lacking the antioxidant enzyme copper-zinc superoxide dismutase (SOD1) show elevated levels of superoxide radicals and are prone to developing cataract when exposed to high levels of glucose in vitro. As superoxide may react further with nitric oxide, generating cytotoxic reactive nitrogen species, we attempted to evaluate the involvement of nitric oxide in glucose-induced cataract. Lenses from SOD1-null and wild-type mice were incubated with high or normal levels of glucose (55.6 and 5.56 mM). A nitric oxide synthase inhibitor (L-NAME) or a nitric oxide donor (DETA/NO) was added to the culture medium. Cataract development was assessed using digital image analysis of lens photographs and cell damage by analyzing the leakage of lactate dehydrogenase. The levels of superoxide radicals in the lenses were also measured. L-NAME was found to reduce cataract development and cell damage in the SOD1-null lenses exposed to high glucose. On the other hand, DETA/NO accelerated cataract development, especially in the SOD1-null lenses. These lenses also showed a higher leakage of lactate dehydrogenase than wild-type controls. We conclude that a combination of high glucose and absence of SOD1 increases the formation of cataract and that nitric oxide probably contributes to this process.
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PMID:Glucose-induced cataract in CuZn-SOD null lenses: an effect of nitric oxide? 1734 36

Alterations of pancreatic antioxidative defense (AD) and possible nitric oxide (NO) role in AD organization of adult rats receiving l-arginine.HCl (2.25%) or N(omega)-nitro-l-arginine methyl ester (L-NAME.HCl, 0.01%) as drinking liquids and maintained at room (22+/-1 degrees C) or low (4+/-1 degrees C) temperature for 45 days were studied. For that purpose, copper, zinc- and manganese superoxide dismutase (CuZnSOD, MnSOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione S-transferase (GST) and glutathione reductase (GR) activities were determined. Cold-induced decrease of CuZnSOD was inhibited with L-NAME, while l-arginine produced the same effect as cold in both supplemented groups. Cold acclimation elevated GSH-Px activity. l-Arginine and L-NAME expressed no effect on GSH-Px in rats kept at room temperature. L-NAME additionally elevated cold-induced GSH-Px activity, l-arginine expressing a similar trend. Cold-induced increase in GST activity was inhibited by L-NAME, while l-arginine inhibited this enzyme in both supplemented groups. Cold acclimation increased GR activity in control and L-NAME-treated group and l-arginine expressed a similar trend. Neither of the treatments affected MnSOD and CAT activities. Cold-induced changes of pancreatic AD were additionally affected by the alterations in l-arginine-NO-producing pathway. Some AD changes in the same direction with l-arginine or L-NAME point to the complexity of nitrogen compounds metabolism and function, accompanied by tissue-specific response.
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PMID:The effects of cold acclimation and nitric oxide on antioxidative enzymes in rat pancreas. 1739 42

Vascular diseases are important clinical complications of diabetes. Advanced glycation end-products (AGE) are mediators of vascular dysfunction, but their effects on vascular smooth muscle cell (VSMC) ROS production are unclear. We studied the source and downstream targets of AGE-mediated ROS and reactive nitrogen species production in these cells. Significant increases in superoxide production in AGE-treated VSMC were measured using lucigenin (7650+/-433 vs 4485+/-424 LU/10(6) cells, p<0.001) or coelenterazine (277,907+/-71,295 vs 120,456+/-4140 LU/10(6) cells, p<0.05) and confirmed by ESR spectroscopy. These signals were blocked by the flavin-containing oxidase inhibitor diphenylene iodonium (DPI). AGE-stimulated NF-kappaB activity was abolished by DPI and the superoxide scavenger MnTBAP. AGE differentially regulated VSMC NADPH oxidase catalytic subunits, stimulating the transcription of Nox1 (201+/-12.7%, p<0.0001), while having no effect on Nox4. AGE also increased 3-nitrotyrosine formation, which was inhibited by MnTBAP, DPI, or the NOS inhibitor L-NAME. Regarding the source of NO, AGE stimulated inducible nitric oxide synthase mRNA (1 vs 9.7+/-3.0, p=0.046), which was abolished by a NF-kappaB inhibitor, SOD, catalase, or siRNA against Nox1. This study establishes that AGE activate iNOS in VSMC through a ROS-sensitive, NF-kappaB-dependent mechanism involving ROS generation by a Nox1-based oxidase.
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PMID:Nox1-based NADPH oxidase-derived superoxide is required for VSMC activation by advanced glycation end-products. 1746 35


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