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)

Lactoferrin (LF) is known as an iron-binding glycoprotein. It has been shown that bovine LF (bLF) is transported into cerebrospinal fluid via blood although its physiological effects in the central nervous system (CNS) are still unclear. In this study, a suppressive effect of bLF on psychological distress was investigated in adult rats. Intraperitoneal injection of bLF (100 mg/kg) reduced stressful behaviors in a conditioned fear-induced freezing test and an elevated plus-maze test. Interestingly, the suppressive effect of bLF was enhanced by pretreatment with electric foot-shock (FS). This suppressive effect of bLF in the elevated plus-maze test was reversed by pretreatment with naloxone, an opioid receptor antagonist, at a dose of 1 mg/kg (ip). N(omega)-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase (NOS) inhibitor, also blocked the suppressive effect of bLF and foot-shock. In addition, combined application of a low dose of bLF (30 mg/kg, ip) and l-arginine (30 and 100 mg/kg, ip) showed significant potentiated effects on psychological stress. These results suggest that bLF has suppressive effects on psychological distress, especially under the condition of moderate stress. Furthermore, it is suggested that bLF possibly activates an endogenous opioidergic system via nitric oxide synthase activation.
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PMID:Suppressive effects of milk-derived lactoferrin on psychological stress in adult rats. 1553 13

Iron overload and enhanced hydroxyl radical (*OH) formation have been implicated as the causative factors of oxidative stress in different organs. Both pro-oxidant and anti-oxidant properties have been reported for nitric oxide (NO) in iron-mediated tissue injury. To determine the contribution of NO to iron-induced renal injury, eight groups of rats (eight in each group) were studied as follows: control (normal saline), L-Arg (L-arginine as a substrate of NO synthase, 400 mg/kg), L-NAME (an inhibitor of NO synthase, 8 mg/kg), Fe (iron dextran, 600 mg/kg), DFO (deferroxamine as a chelator of iron, 150 mg/kg), Fe+L-Arg, Fe+L-NAME, DFO+L-Arg. Twenty-four hours after the injections, blood samples were taken and kidneys removed for biochemical analysis. Plasma creatinine and urea were used to stimulate renal function. Renal tissue and plasma vitamin E levels, the most important endogenous fat soluble antioxidant, were measured by HPLC and UV detection. In this study, renal function was markedly reduced in the Fe group compared to controls (creatinine, 1.02+/-0.05 mg/dL versus 0.78+/-0.04 P <0.05; urea, 49.59+/-1.69 mg/dL versus 40.75+/-0.86, P <0.01). Vitamin E levels were significantly lower in the Fe group compared to controls (plasma P <0.01; renal tissue P <0.05). Administration of L-Arg to Fe-treated groups prevented these reductions. L-NAME increased iron-induced toxicity significantly, demonstrated by further reduction in the vitamin E levels and renal function compared to the Fe group alone. We concluded that NO plays an important role in protecting the kidney from iron-induced nephrotoxicity. NO synthase blockade enhances iron-mediated renal toxicity in this model.
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PMID:The role of nitric oxide in iron-induced rat renal injury. 1562 79

Labedipinedilol-A, a novel dihydropyridine-type calcium antagonist, has been shown to induce hypotension and vasorelaxation. The objective of the present study was to investigate the effect of labedipinedilol-A on vascular function of rat aortic rings and cultured human umbilical vein endothelial cells (HUVECs). Labedipinedilol-A induced vasorelaxation in rat aortic rings that had been precontracted with phenylephrine in a concentration-dependent manner. This labedipinedilol-A-induced relaxation was significantly reduced by endothelium removal and by exposure to L-NG-nitroarginine methyl ester (L-NAME), methylene blue, or 1H-[1,2,4]oxadiazolol[4,3,a]quinoxalin-1-one (ODQ). In addition, the cyclic GMP content was significantly increased by labedipinedilol-A, which was inhibited by L-NAME in aorta. In cultured HUVECs, labedipinedilol-A induced concentration-dependent formation of NO and Ca2+ influx, and it increased the abundance of endothelial NO synthase (eNOS) protein. Furthermore, labedipinedilol-A suppressed basal, 10% FBS- and thrombin-stimulated endothelin-1 production, which were reversed by pretreatment with L-NAME, demonstrating that NO was able to inhibit production of ET-1 in HUVECs. Labedipinedilol-A significantly protected cultured HUVECs against dihydroxyfumarate/iron ion-induced decrease of glutathione and cell death. Moreover, labedipinedilol-A also inhibited iron-induced lipid peroxidation in rat brain homogenate and scavenged 2,2'-azobis (2-amidinopropane) dihydrochloride-derived peroxy radicals. Labedipinedilol-A acts as lacidipine with additional antioxidant effects and can protect endothelial cells against free radical-induced lipid peroxidation and cell injury. Our results indicate that the endothelium-dependent vasorelaxation by labedipinedilol-A is mediated through Ca2+-dependent activation of NO synthase and stimulation of NO/cyclic GMP pathway.
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PMID:The vasorelaxing action of labedipinedilol-A involves endothelial cell-derived NO and eNOS expression caused by calcium influx. 1572 48

Arsenic is a naturally occurring element that is present in food, soil, and water. Inorganic arsenic can accumulate in human skin and is associated with increased risk of skin cancer. Oxidative stress due to arsenic exposure is proposed as one potential mode of carcinogenic action. The purpose of this study is to investigate the specific reactive oxygen and nitrogen species that are responsible for the arsenic-induced oxidative damage to DNA and protein. Our results demonstrated that exposure of human keratinocytes to trivalent arsenite caused the generation of 8-hydroxyl-2'-deoxyguanine (8-OHdG) and 3-nitrotyrosine (3-NT) in a concentration- and time-dependent manner. Pentavalent arsenate had similar effects, but to a significantly less extent. The observed oxidative damage can be suppressed by pre-treating cells with specific antioxidants. Furthermore, we found that pre-treating cells with Nomega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), or with 5,10,15,20-tetrakis (N-methyl-4'-pyridyl) porphinato iron (III) chloride (FeTMPyP), a decomposition catalyst of peroxynitrite, suppressed the generation of both 8-OHdG and 3-NT, which indicated that peroxynitrite, a product of the reaction of nitric oxide and superoxide, played an important role in arsenic-induced oxidative damage to both DNA and protein. These findings highlight the involvement of peroxynitrite in the molecular mechanism underlying arsenic-induced human skin carcinogenesis.
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PMID:Inorganic arsenic compounds cause oxidative damage to DNA and protein by inducing ROS and RNS generation in human keratinocytes. 1628 19

The electron spin resonance (ESR) spin-trapping technique coupled with iron-dithiocarbamate complexes is one of the most specific methods for nitric oxide (NO) detection. In this study, we applied this method for the evaluation of the substrate and the inhibitors of NO synthase (NOS). A three-line ESR signal was detected from the mixture of inducible NOS (iNOS), l-arginine (Arg), nicotinamide adenine dinucleotide phosphate (NADPH), tetrahydrobiopterin, dithiothreitol, and Fe(2+)-N-(dithiocarboxy) sarcosine (DTCS-Fe), and the signal intensity increased time-dependently. The signal was not observed by excluding either Arg or NADPH, and it was decreased by the addition of hemoglobin, which is an NO scavenger, and N(G)-monomethyl-l-arginine (l-NMMA), N(G)-nitro-l-arginine (l-NAME), and aminoguanidine (AG), which are NOS inhibitors, depending on the concentration. In comparison with l-NAME and AG, l-NMMA strongly inhibited iNOS activity. By using this method, the K(m) value of Arg and the K(i) value of l-NMMA for iNOS were determined to be 12.6 and 6.1muM, respectively. These values are consistent with the reported values measured by the oxyhemoglobin and citrulline assays. These results suggest that the ESR spin-trapping technique coupled with the iron-dithiocarbamate complex can be applied for the evaluation of substrates and inhibitors of NOS, and it would be a powerful tool due to its simplicity and high specificity to NO.
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PMID:Application of electron spin resonance spin-trapping technique for evaluation of substrates and inhibitors of nitric oxide synthase. 1636 Jan 10

The long-term effects of nitric oxide (NO) on cell susceptibility to photodynamic killing have been studied, using a human breast tumor line (COH-BR1). Subconfluent cells were exposed to a nonlethal dose of spermine NONOate (SPNO, 0.2 mM) and 20 h later were metabolically sensitized with protoporphyrin IX (PpIX) by incubating with 5-aminolevulinic acid. PpIX overproduced in mitochondria was allowed to diffuse to peripheral sites, including plasma membrane, after which a photooxidative challenge was imposed. Active (but not decomposed) SPNO made cells substantially more resistant to necrotic photokilling than non-SPNO-treated controls. A similar response to a tert-butyl hydroperoxide challenge was observed. Hyperresistance was detected approximately 8 h post-SPNO, maximized after approximately 20 h, and reflected diminished oxidant accumulation, as determined with 2',7'-dichlorofluorescein. Intracellular free iron determined with the fluorescent probe calcein rose to approximately 160% of the control level 6 h after SPNO, but declined to approximately 70% after 24 h. Immunoblot analyses revealed a rapid early (approximately 2 h post-NO) increase in heme oxygenase-1 level, followed by a gradual (4-20 h post-NO) increase in ferritin. Upregulation of these proteins is consistent with a cytoprotective mechanism involving mobilization of "signaling" iron. Preactivated RAW 264.7 macrophages on microporous inserts also induced a long-term photoresistance in underlying PpIX-sensitized COH-BR1 cells. This response was abolished by L-NAME, indicating that NO from induced nitric oxide synthase was involved. The NO effects described are entirely novel in the context of photooxidative stress and provide new insights into how NO might affect antitumor photodynamic therapy (PDT).
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PMID:Nitric oxide-induced resistance to lethal photooxidative damage in a breast tumor cell line. 1663 22

Chronic iron overload (CIO) enhances nitric oxide (*NO) production in the liver, which may represent a hepatoprotective mechanism against CIO toxicity. In order to test this hypothesis, the influence of CIO (diet enriched with 3% (wt/wt) carbonyl-iron for 8 weeks) in the absence or presence of the (*)NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) on NOS activity, extracellular signal-regulated kinase (ERK1/2) and NF-kappaB activation was studied, in relation to ferritin expression and liver morphology. CIO increased liver NOS activity, ERK1/2 phosphorylation, NF-kappaB DNA binding, and ferritin expression, with normal liver histology. These changes were suppressed by combined CIO and L-NAME treatment, with the resulting inflammatory response of the liver. It is concluded that (*)NO response induced by CIO represents a molecular mechanism affording protection against iron toxicity, which is related to both the activation of the ERK/NF-kappaB pathway involving inducible NOS expression and ferritin upregulation, changes that may be interrelated.
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PMID:Hepatoprotective role of nitric oxide in an experimental model of chronic iron overload. 1687 48

Dexrazoxane is used clinically to reduce the cardiotoxicity of anthracycline cancer chemotherapeutic agents, acting by an iron-chelating antioxidant mechanism. In a study designed to explore the possible mechanism of the recently described neuroprotective effect of the drug in cerebral ischemia, its influence on vascular reactivity was determined in rat aortic rings. Dexrazoxane was found to be devoid of direct contractile or relaxant activity and to have no influence on responses to acetylcholine or histamine (relaxation), or to angiotensin or serotonin (contraction). In contrast, it decreased contractions to norepinephrine, as evidenced by rightward displacement of the concentration-response curves. The effect was prevented by the removal of the endothelium and by the alpha(2)-adrenoceptor antagonist yohimbine; it was partially antagonized by the endothelium-derived depolarizing factor inhibitor clotrimazole, but was not affected by L-NAME or indomethacin, inhibitors of endothelial nitric oxide and prostacyclin production. The anti-contractile effect did not occur in rings stimulated with the alpha(1)-adrenoceptor agonist phenylephrine. It was concluded that dexrazoxane opposes norepinephrine vascular contraction by enhancing endothelial alpha(2)-adrenoceptor-mediated release of relaxing factor(s). The drug could thus offset the deleterious vasoconstriction elicited by the increased circulating catecholamines present during cerebral ischemia, and by this mechanism produce neuroprotection.
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PMID:Antivasoconstrictor effect of the neuroprotective agent dexrazoxane in rat aorta. 1700 88

The role of nitric oxide (NO) in acute renal failure (ARF) is debatable. In the present study, we investigated the effect of acute administration of NO donor, Sodium nitroprusside (SNP), L-Arginine (L-Arg) and NO synthase inhibitor, N(omega)-L-arginine methyl ester (L-NAME) in Fe-NTA induced renal toxicity. Rats were pretreated with SNP (2.5 mg/kg i.p), L-Arg (125 mg/kg, i.p.) and L-NAME (10 mg/kg, i.p.) prior to administration of Fe-NTA (8 mg iron/kg body weight, i.p.) to determine the urea and creatinine levels along with biochemical analysis of oxidative stress. Fe-NTA administration markedly increased the BUN and serum creatinine level which was coupled with a marked lipid peroxidation, decreased levels of reduced glutathione and total nitric oxide levels of rat kidneys coupled with significant morphological alterations. It also resulted in the significant increase in tumor necrosis factor-alpha (TNF-alpha) in serum. Concomitant treatment with SNP and L-Arg significantly reduced the serum creatinine and BUN levels, reduced lipid peroxidation in a significant manner, restored levels of reduced glutathione, increased total nitric oxide levels and restored the normal morphology. Pretreatment with SNP and L-Arg attenuated the levels of TNF-alpha in serum in a significant manner. Prior administration of L-NAME reversed the protective effects produced by SNP and L-Arg. Present findings strongly suggest that nitric oxide plays a significant role in the pathophysiology of iron-induced renal failure and administration of NO donors can be valuable in the treatment of ARF.
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PMID:Sodium nitroprusside and L-arginine attenuates ferric nitrilotriacetate-induced oxidative renal injury in rats. 1728 Jul 60

Manganese in excess is neurotoxic and causes a CNS disorder that resembles Parkinson's disease (manganism). Manganese highly accumulates in astrocytes, which renders these cells more vulnerable to its toxicity. Consistent with this vulnerability, manganese has been shown to cause histopathological changes in astrocytes (Alzheimer type II change), generates oxidative stress and bring about mitochondrial dysfunction, including the induction of the mitochondrial permeability transition (mPT) in astrocytes. In addition to manganism, increased brain levels of manganese have been found in hepatic encephalopathy, a chronic neurological condition associated with liver dysfunction, wherein Alzheimer type II astrocytic changes are also observed. As low-grade brain edema, possibly secondary to astrocyte swelling, has been reported in hepatic encephalopathy, we hypothesized that manganese may contribute to such edema. We therefore exposed cultured astrocytes to manganese (Mn(3+)) acetate (25 and 50microM) for different time periods and examined for changes in cell volume. Manganese dose-dependently induced astrocyte swelling; such swelling was first observed at 12h (28%), which further increased (54%) at later time points (24-48h). Pretreatment of astrocyte cultures with antioxidants, including vitamin E, the spin trapping agent PBN, and the iron-chelating agent desferroximine, as well as the nitric oxide synthase inhibitor l-NAME, all significantly blocked (50-80%) astrocyte swelling caused by manganese, suggesting that oxidative/nitrosative stress is involved in the mechanism of such swelling. Cyclosporin A, an inhibitor of mPT also blocked (90%) manganese-induced astrocyte swelling. The data indicate that manganese exposure results in astrocyte swelling and such swelling, at least in part, may be caused by oxidative stress and/or mPT. Astrocyte swelling by manganese may represent an important aspect of manganese neurotoxicity, and may be a factor in low-grade brain edema associated with chronic hepatic encephalopathy.
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PMID:Manganese induces cell swelling in cultured astrocytes. 1740 48


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