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PubMed2004

Application of the measurement of oxidized pyridine dinucleotides with high-performance liquid chromatography-fluorescence detection to assay the uncoupled oxidation of NADPH by neuronal nitric oxide synthase.

A rapid and sensitive high-performance liquid chromatography method has been developed for the measurement of oxidized pyridine dinucleotides (NAD+, NADP+) in biological samples following fluorescence derivatization. Under strongly alkaline conditions the pyridinium ring of the nicotinamide moiety reacts with carbonyl compounds, resulting in stable fluorescent products. Upon subsequent addition of concentrated formic acid and treatment with heat, this fluorescence is further amplified and is shifted to higher-wavelength regions. From among the ketones assayed (acetone, ethylmethyl ketone, acetophenone) the condensation product with acetophenone possesses the highest molar relative fluorescence, thus allowing the most sensitive detection in our experimental setup (limit of detection: 0.02pmol/50 microliter injected volume). The fluorescent products have been separated on a reverse-phase C-18 column using 0.1M citric acid (pH 3.2)/acetonitrile (92/8, v/v) as mobile phase. Our method is suitable for assaying NADH- and NADPH-dependent enzyme reactions by quantifying oxidized coenzyme products. As an example, the activity of neuronal nitric oxide synthase (nNOS), a NADPH-requiring enzyme, has been assessed by measuring the products NADP+ and l-citrulline at various substrate (l-arginine) concentrations. The rate of the uncoupled NADPH oxidation by nNOS can be estimated from the ratio of NADP+/l-citrulline produced.

Animals↗
PubMed1998

Oxidant stress, anti-oxidants, nitric oxide and essential fatty acids in peptic ulcer disease.

In patients with duodenal ulcer (DU), the plasma levels of nitrite and lipid peroxides, the anti-oxidant content of red cells and plasma phospholipid fatty acid analysis were performed both before and after healing of the ulcer following treatment with lansoprazole, a proton pump inhibitor. These results showed that during the phase of active DU, the concentrations of antioxidants (superoxide dismutase, SOD, catalase and glutathione peroxidase) in red cells were low where as those of lipid peroxides and nitric oxide were high. Of the fatty acids measured, the concentration of palmitic acid (16:0) was increased during the active ulcer phase whereas those of arachidonic acid, alpha-linolenic acid and docosahexaenoic acid were low. These biochemical abnormalities reverted to normal following healing of the ulcer with lansoprazole. These results coupled with the observation that polyunsaturated fatty acids (PUFAs) can inhibit the growth of Helicobacterpylori and heal the ulcer suggest that free radicals, anti-oxidants, nitric oxide and PUFAs may play a significant role in the pathogenesis of DU. If this is true, it suggests that PUFAs can be exploited as potential anti-peptic ulcer drugs.

Adolescent↗
PubMed1999

Nitrite- and peroxide-dependent oxidation pathways of dopamine: 6-nitrodopamine and 6-hydroxydopamine formation as potential contributory mechanisms of oxidative stress- and nitric oxide-induced neurotoxicity in neuronal degeneration.

In the presence of nitrite ions (NO(2)(-)) in phosphate buffer (pH 7. 4) and at 37 degrees C, dopamine was oxidized by a variety of hydrogen peroxide (H(2)O(2))-dependent enzymatic and chemical systems to give, in addition to black melanin-like pigments via 5, 6-dihydroxyindoles, small amounts of the potent neurotoxin 6-hydroxydopamine (1) and of 6-nitrodopamine (2), a putative reaction product of dopamine with NO-derived species. Treatment of 0. 5 or 1 mM dopamine with horseradish peroxidase (HRP) or lactoperoxidase (LPO) in the presence of 1 or 2 mM H(2)O(2) with NO(2)(-) at a concentration of 0.5-10 mM resulted in the formation of 1 and 2 in up to 8 and 2 microM yields, respectively, depending on the substrate concentration and the NO(2)(-):H(2)O(2) ratio. Nitration and hydroxylation of 0.1 mM dopamine was observed with 1 mM NO(2)(-) using HRP and the D-glucose/glucose oxidase system to generate H(2)O(2) in situ. In the presence of NO(2)(-)-, Fe(2+)-, or Fe(2+)/EDTA-promoted oxidations of dopamine with H(2)O(2) also led to the formation of 1 and 2, the apparent product ratios varying with peroxide concentration and the partitioning of the metal between EDTA and catecholamine chelates. In the presence of NO(2)(-), Fe(2+)-promoted autoxidation of dopamine gave 2 but no detectable 1. When injected into the brains of laboratory rats, 2 caused sporadic behavioral changes, indicating that it could elicit a neurotoxic response, albeit to a lower extent than 1. Model experiments using tyrosinase as an oxidizing system and mechanistic considerations suggested that formation of 2 does not involve reactive nitrogen radicals but results mainly from nucleophilic attack of NO(2)(-) to dopamine quinone. Generation of 1, on the other hand, may be derives from different H(2)O(2)-dependent pathways. Collectively, these results outline a complex interplay of NO(2)(-)- and peroxide-dependent oxidation pathways of dopamine, which may contribute to impair dopaminergic neurotransmission and induce cytotoxic processes in neurodegenerative disorders.

Animals↗
PubMed1997

Superoxide modulates the oxidation and nitrosation of thiols by nitric oxide-derived reactive intermediates. Chemical aspects involved in the balance between oxidative and nitrosative stress.

Thiol-containing proteins are key to numerous cellular processes, and their functions can be modified by thiol nitrosation or oxidation. Nitrosation reactions are quenched by O-2, while the oxidation chemistry mediated by peroxynitrite is quenched by excess flux of either NO or O-2. A solution of glutathione (GSH), a model thiol-containing tripeptide, exclusively yielded S-nitrosoglutathione when exposed to the NO donor, Et2NN(O)NONa. However, when xanthine oxidase was added to the same mixture, the yield of S-nitrosoglutathione dramatically decreased as the activity of xanthine oxidase increased, such that there was a 95% reduction in nitrosation when the fluxes of NO and O-2 were nearly equivalent. The presence of superoxide dismutase reversed O-2-mediated inhibition, while catalase had no effect. Increasing the flux of O-2 yielded oxidized glutathione (GSSG), peaking when the flux of NO and O-2 were approximately equivalent. The results suggest that oxidation and nitrosation of thiols by superoxide and NO are determined by their relative fluxes and may have physiological significance.

Free Radicals↗
PubMed1994

Nitric oxide inhibits neuronal nitric oxide synthase by interacting with the heme prosthetic group. Role of tetrahydrobiopterin in modulating the inhibitory action of nitric oxide.

The objective of this study was to elucidate the mechanism by which nitric oxide (NO) inhibits NO synthase. Previous studies revealed that NO inhibits unpurified preparations of NO synthase. In the present study, the mechanism by which NO inhibits purified neuronal NO synthase from rat cerebellum was examined. The rate of L-citrulline formation from L-arginine was non-linear despite the presence of excess substrate and cofactors and was further inhibited by 30% by 200 units/ml superoxide dismutase. In contrast, 30 microM oxyhemoglobin increased NO synthase activity by 2-fold and made the reaction rate linear. These observations were consistent with the hypothesis that enzymatically generated NO inhibits NO synthase activity. Exogenous NO (0.1-10 microM) (but not NO2, nitrite, or nitrate) also inhibited NO synthase, and enzyme inhibition was not competitive with L-arginine. NO synthase inhibition by NO and other heme ligands supports the view that heme is involved in the catalytic activity of NO synthase. Oxyhemoglobin prevented but could not reverse enzyme inhibition by NO. NO synthase inhibition by NO was markedly diminished and reversed, however, by tetrahydrobiopterin (50 microM) or a tetrahydrobiopterin-regenerating system, and the latter made the reaction rate linear. In contrast, NO synthase inhibition by NO was markedly enhanced by heme oxidants (10 microM methylene blue; 3 microM ferricyanide), and these oxidants directly inhibited NO synthase activity. These observations suggest that NO interacts with enzyme-bound ferric heme to inhibit NO synthase activity. In support of this view, NO inhibited enzyme activity in the absence of turnover, when the heme iron is in the ferric state, and this inhibition was reversed by tetrahydrobiopterin. Therefore, the oxidation state of heme iron appears to be one important determinant for the inhibitory action of NO, and tetrahydrobiopterin may increase NO synthase activity by diminishing the inhibitory action of NO.

Amino Acid Oxidoreductases↗
PubMed2003

Preparation and characterization of polypseudorotaxanes based on block-selected inclusion complexation between poly(propylene oxide)-poly(ethylene oxide)-poly(propylene oxide) triblock copolymers and alpha-cyclodextrin.

A series of new polypseudorotaxanes were synthesized in high yields when the middle poly(ethylene oxide) (PEO) block of poly(propylene oxide)-poly(ethylene oxide)-poly(propylene oxide) (PPO-PEO-PPO) triblock copolymers was selectively recognized and included by alpha-cyclodextrin (alpha-CD) to form crystalline inclusion complexes (ICs), although the middle PEO block was flanked by two thicker PPO blocks, and a PPO chain had been previously thought to be impenetrable to alpha-CD. X-ray diffraction studies demonstrated that the IC domains of the polypseudorotaxanes assumed a channel-type structure similar to the necklace-like ICs formed by alpha-CD and PEO homopolymers. Solid-state CP/MAS (13)C NMR studies showed that the alpha-CD molecules in the polypseudorotaxanes adopted a symmetrical conformation due to the formation of ICs. The compositions and stoichiometry of the polypseudorotaxanes were studied using (1)H NMR, and a 2:1 (ethylene oxide unit to alpha-CD) stoichiometry was found for all polypseudorotaxanes although the PPO-PEO-PPO triblock copolymers had different compositions and block lengths, suggesting that only the PEO block was closely included by alpha-CD molecules, whereas the PPO blocks were uncovered. The hypothesis was further supported by the differential scanning calorimetry (DSC) studies of the polypseudorotaxanes. The glass transitions of the PPO blocks in the polypseudorotaxanes were clearly observed because they were uncovered by alpha-CD and remained amorphous, whereas the glass-transition temperatures increased, because the molecular motion of the PPO blocks was restricted by the hard crystalline phases of the IC domains formed by alpha-CD and the PEO blocks. The thermogravimetric analysis (TGA) revealed that the polypseudorotaxanes had better thermal stability than their free components due to the inclusion complexation. Finally, the kinetics of the threading process of alpha-CD onto the copolymers was also studied. The findings reported in this article suggested interesting possibilities in designing other cyclodextrin ICs and polypseudorotaxanes with block structures.

Cyclodextrins↗
PubMed1999

Inhibition of xanthine oxidase and xanthine dehydrogenase by nitric oxide. Nitric oxide converts reduced xanthine-oxidizing enzymes into the desulfo-type inactive form.

Xanthine oxidase (XO) and xanthine dehydrogenase (XDH) were inactivated by incubation with nitric oxide under anaerobic conditions in the presence of xanthine or allopurinol. The inactivation was not pronounced in the absence of an electron donor, indicating that only the reduced enzyme form was inactivated by nitric oxide. The second-order rate constant of the reaction between reduced XO and nitric oxide was determined to be 14.8 +/- 1.4 M-1 s-1 at 25 degrees C. The inactivated enzymes lacked xanthine-dichlorophenolindophenol activity, and the oxypurinol-bound form of XO was partly protected from the inactivation. The absorption spectrum of the inactivated enzyme was not markedly different from that of the normal enzyme. The flavin and iron-sulfur centers of inactivated XO were reduced by dithionite and reoxidized readily with oxygen, and inactivated XDH retained electron transfer activities from NADH to electron acceptors, consistent with the conclusion that the flavin and iron-sulfur centers of the inactivated enzyme both remained intact. Inactivated XO reduced with 6-methylpurine showed no "very rapid" spectra, indicating that the molybdopterin moiety was damaged. Furthermore, inactivated XO reduced by dithionite showed the same slow Mo(V) spectrum as that derived from the desulfo-type enzyme. On the other hand, inactivated XO reduced by dithionite exhibited the same signals for iron-sulfur centers as the normal enzyme. Inactivated XO recovered its activity in the presence of a sulfide-generating system. It is concluded that nitric oxide reacts with an essential sulfur of the reduced molybdenum center of XO and XDH to produce desulfo-type inactive enzymes.

Animals↗
PubMed1992

Comparison of 2,5,5-trimethyl-1-pyrroline-N-oxide (M3PO) and 3,3,5,5-tetramethyl-1-pyrroline-N-oxide (M4PO) with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as spin traps.

2,5,5-Trimethyl-1-pyrroline-N-oxide (M3PO) and 3,3,5,5-tetramethyl-1-pyrroline-N-oxide (M4PO) were examined for their potential as spin traps used in biological samples, and the results obtained for M3PO and M4PO were compared with those of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) reported previously. The rate constants for the reactions of M3PO and M4PO with hydroxyl radicals were in the same order of that constant of DMPO. The hyperfine splitting constants of M4PO spin adducts were as informative as those of DMPO adducts. In the presence of ferric ions, M3PO and M4PO formed 2-hydroxy-2,5,5-dimethyl-1-pyrrolidinyloxy (M3PO-OH) and 2-hydroxy-3,3,5,5-tetramethyl-1-pyrrolidinyloxyl (M4PO-OH), respectively, by the nucleophilic addition of a water molecule, as we have already reported for DMPO. M4PO-OH was subjected to oxidation by ferric ions with a rate much slower than that for DMPO-OH, while M3PO-OH was not. The results indicate that M4PO is a spin trap suitable for biological applications and that nitrones having a methyl group at C2 represent improved spin traps.

Cyclic N-Oxides↗
PubMedDate not supplied

N-hydroxylation of the antiprotozoal drug pentamidine catalyzed by rabbit liver cytochrome P-450 2C3 or human liver microsomes, microsomal retroreduction, and further oxidative transformation of the formed amidoximes. Possible relationship to the biological oxidation of arginine to NG-hydroxyarginine, citrulline, and nitric oxide.

Previous investigations have shown that the antiprotozoal drug pentamidine is N-hydroxylated by rabbit and rat liver microsomal fractions. Indirect evidence for the participation of the cytochrome P-450 enzyme system was obtained. In this study, rabbit liver cytochrome P-450 2C3 is shown by reconstitution experiments with highly purified variants of P-450 2C3 isolated from rabbit liver and purified variants of P-450 2C3 expressed by recombinant Escherichia coli to be a microsomal pentamidine N-hydroxylase. The two variants, P-450 2C3 (6 beta H) and P-450 2C3 (6 beta L), are equally efficient for the formation of the monoamidoxime derivative of pentamidine. N-hydroxypentamidine is further oxidized to the respective amide by reconstituted rabbit liver P-450 enzyme systems involving the oxidase and peroxidase activities of this enzyme. Formation of nitric oxide [(NO); endothelium-derived relaxing factor] during this oxidation is shown by the detection of the cytochrome P-420-Fe(II)-NO complex by visible difference spectroscopy. The possibility for the N-hydroxylation of pentamidine to the corresponding amidoximes and subsequent oxidative conversion to the respective amide derivatives is comparable with the physiological transformation of arginine to citrulline via N-hydroxyarginine with liberation of NO (endothelium-derived relaxing factor). The N-hydroxylated derivatives of pentamidine are easily retroreduced by microsomal fractions from rabbit liver. NADH is preferred to NADPH as cofactor for this reduction, and the reaction is strongly suppressed by the addition of N-methylylhydroxylamine. The N-hydroxylation of pentamidine and the retroreduction are also catalyzed by human liver microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Expression of adhesion molecules by human endothelial cells exposed to oxidized low density lipoprotein. Influences of degree of oxidation and location of oxidized LDL.

The main objective of this study was to determine the influence of the degree of low density lipoprotein (LDL) oxidation and the location of oxidized LDL (oxLDL) on expression of adhesion molecules on endothelial cells (EC). OxLDL preparations 1-4 with different degrees of oxidative modification were studied. All preparations of oxLDL, after addition to the medium, stimulated the expression of intercellular adhesion molecule-1 (ICAM-1) by human umbilical vein endothelial cells (HUVEC) as determined by cell-ELISA. Concentration-dependent studies examining ICAM-1 expression by HUVEC showed that the minimal concentration of oxLDL which significantly stimulated ICAM-1 expression was 5 microg/ml, suggesting that the predicted physiological concentration of oxLDL in plasma may be not high enough to elicit a substantial increase of ICAM-1 expression in EC. In contrast, very small amounts (0.15 microg/well) of oxLDL-3 and 4, the more heavily oxidized LDL preparations, stimulated effectively ICAM-1 expression by HUVEC when located below the endothelial cell monolayer by immobilizing to type I collagen. The results suggest that the increased expression of ICAM-1 induced by accumulated oxLDL may be one of the mechanisms by which oxLDL contributes to atherogenesis.

Cells, Cultured↗
PubMed1994

The role of the glucose/fatty acid cycle in the selective modulation of non-oxidative and oxidative glucose disposal by oxidative muscle in late pregnancy.

Physiological insulin stimulation (induced by re-feeding) in late (19 to 20 days) pregnancy in the rat led to only partial reversal of starvation-induced increases in circulating fatty acid concentrations. The impaired suppression of adipose tissue lipolysis was associated with a clear attenuation of the activation of PDHa activity in oxidative skeletal muscles (diaphragm, soleus and adductor longus) in response to physiological insulin stimulation. In contrast, effects of late pregnancy to suppress glucose utilization were only modest in oxidative skeletal muscles, where a predominate fate of glucose under physiological insulin stimulation is glycogen formation. The ability of the pregnant rat to sustain glycogen repletion during physiological insulin stimulation was retained. Glucose utilization by the heart, which in virgin rats is particularly sensitive to increases in lipid-fuel supply and oxidation, bore a significant inverse relationship with the plasma fatty acid concentrations in late-pregnant rats. We conclude that an elevation in circulating fatty acid concentrations in late pregnancy provokes changes in glucose utilization by cardiac and skeletal muscle which are consistent with the operation of the glucose-fatty acid cycle. Importantly, these effects pertain under physiological hyperinsulinaemia. The relative insensitivity of glucose utilization by oxidative skeletal muscle to late pregnancy under conditions of physiological insulin stimulation presumably reflects the predominant use of glucose as a substrate for glycogen synthesis rather than as an energy substrate.

Animals↗
PubMed1990

Neuromuscular and cardiovascular effects of mivacurium chloride (BW B109OU) during nitrous oxide-narcotic, nitrous oxide-halothane and nitrous oxide-isoflurane anesthesia in surgical patients.

One hundred seventeen adult surgical patients were studied to compare neuromuscular and cardiovascular effects of mivacurium chloride during nitrous oxide-narcotic (BAL, n = 45) nitrous oxide-halothane (HAL, n = 27) and nitrous oxide-isoflurane (ISF, n = 45) anesthesia. Anesthesia was maintained with nitrous oxide (60%-70%) and oxygen (30%-40%) with end-tidal concentrations of halothane or isoflurane to yield a total MAC of approximately 1.25, or with supplemental fentanyl and thiopental as clinically indicated. Twitch response of the adductor pollicis muscle was elicited by supramaximal square wave pulses of 0.2 msec duration at a frequency of 0.15 Hz (Grass S44 stimulator) to the ulnar nerve and quantitated by a Grass FT10 transducer. Nine patients in each of the HAL and ISF groups received one of four doses of mivacurium (0.03, 0.05, 0.10 or 0.15 mg/kg). Ninety patients in the balanced anesthesia group received one of seven doses of mivacurium (0.03, 0.04, 0.05, 0.08, 0.15, 0.20, 0.25 mg/kg). The ED50, ED75 and ED95 of mivacurium in each group were estimated from linear regression plots of log dose versus probit of maximum percentage depression of twitch height. The ED50, ED75 and ED95 for halothane and isoflurane are 0.040, 0.053 and 0.081 and 0.037, 0.043 and 0.053, respectively. The ED50, ED75, and ED95 for the balanced group are 0.039, 0.050, and 0.073 mg/kg respectively. There was no significant difference between the slopes of the HAL and BAL inhalation anesthetic dose-response curves. The slope of the ISF group was significantly than the slope of the BAL group. Intercepts of the HAL and BAL curves were not different. The isoflurane curve's intercept was significantly less than the other groups' intercepts, lying above the halothane curve, but below the BAL curve. For the 0.05 mg/kg dose, maximum block was greater in the ISF group (89.1 +/- 2.7%, n = 9) than in the HAL (70.3 +/- 7.6%, n = 9) or BAL (67.7 +/- 6.4%, n = 9) groups. At higher doses of mivacurium, isoflurane produces a greater potentiation of neuromuscular block than halothane or balanced anesthesia. There were no significant cardiovascular changes seen in any group following mivacurium doses up to 0.15 mg/kg (approximately 2xED95).

Adult↗
PubMed1998

Generation of nitric oxide by a nitrite reductase activity of xanthine oxidase: a potential pathway for nitric oxide formation in the absence of nitric oxide synthase activity.

Nitric oxide (NO) synthesis is well-known to result from the oxidation of L-arginine by a family of NO synthases (NOS). However, under hypoxic conditions this mechanism of NO synthesis may be impaired and NO is formed by a NOS independent mechanism. This study was designed to examine the reduction of nitrite to NO by xanthine oxidase (XO) under hypoxia, because the bacterial nitrate/nitrite reductases have structural similarity to XO. We found that both purified and tissue containing XO catalyze the reduction of nitrite to NO, as demonstrated using a chemiluminescent NO meter. This redox reaction requires NADH as an electron donor, and is oxygen independent. The inhibitory profiles suggest that reduction of nitrite takes place at the molybdenum center of XO whilst NADH is oxidized at the FAD center. Heparin binding of XO caused an increase in the catalysis of nitrite reduction. The XO-catalyzed generation of NO may be important in redistribution of blood flow to ischaemic tissue as a supplement to NOS, since both nitrite and NADH have been shown to be elevated in hypoxic tissue.

Anaerobiosis↗
PubMed2006

Pomegranate juice protects nitric oxide against oxidative destruction and enhances the biological actions of nitric oxide.

Pomegranate juice (PJ), which is a rich source of potent flavonoid antioxidants, was tested for its capacity to protect nitric oxide (NO) against oxidative destruction and enhance the biological actions of NO. Employing chemiluminescence headspace analysis, PJ was found to be a potent inhibitor of superoxide anion-mediated disappearance of NO. PJ was much more potent than Concord grape juice, blueberry juice, red wine, ascorbic acid, and DL-alpha-tocopherol. As little as 3 microl of a 6-fold dilution of PJ, in a reaction volume of 5000 microl, produced a marked antioxidant effect, whereas 300 microl of undiluted blueberry juice or nearly 1000 microl of undiluted Concord grape juice were required to produce similar effects. PJ and other antioxidant-containing products were found to augment the anti-proliferative action of NO (DETA/NO) on vascular smooth muscle cell (rat aorta) proliferation. PJ was much more effective than the other products tested and elicited no effects when tested alone in the absence of added NO. Similarly, neither PJ nor the other products enhanced the anti-proliferative action of alpha-difluoromethylornithine, a stable substance that inhibits cell growth by NO-independent mechanisms. In order to determine whether PJ is capable of increasing the production of NO by vascular endothelial cells, PJ was tested for its capacity to upregulate and/or activate endothelial NO synthase (eNOS) in bovine pulmonary artery endothelial cells. PJ elicited no effects on eNOS protein expression or catalytic activity. Moreover, PJ did not enhance promoter activity in the eNOS gene (COS-7 cells transfected with eNOS). These observations indicate that PJ possesses potent antioxidant activity that results in marked protection of NO against oxidative destruction, thereby resulting in augmentation of the biological actions of NO.

Animals↗
PubMedDate not supplied

Nitric oxide synthase inhibition by haem oxygenase decreases macrophage nitric-oxide-dependent cytotoxicity: a negative feedback mechanism for the regulation of nitric oxide production.

Nitric oxide (NO) production in macrophages by inducible nitric oxide synthase (NOS2) has multiple tissue damaging effects and is involved in the pathogenesis of inflammation and graft rejection. Haem oxygenase (HmOx) is the enzyme which degrades haem. Its inducible isoform, HmOx1, was recently shown to increase cellular resistance against oxidative stress and to decrease inflammation and graft rejection. Since haem is an essential cofactor for NOS2 activity, we investigated the effects of HmOx1-induction upon NO secretion in macrophages. We induced HmOx1 in BALB/c bone-marrow-derived macrophages by short-term exposure to haemin (20 micromol/l, 30 min); then we incubated them for 24 h to allow maximal expression of HmOx1 activity. Next, we activated the macrophages with lipopolysaccharide (LPS) and measured their NO production and their NO-dependent cytotoxicity against P815 cells. We found that HmOx induction 24 h before LPS activation in mouse macrophages suppresses their production of NO, while HmOx inhibition (with zinc protoporphyrin) increases NO secretion. NOS2 inhibition is reflected by the decrease of macrophage NO-dependent cytotoxicity against the P815 targets. We therefore propose that HmOx1 is a physiological inhibitor of NOS2 in activated macrophages because it decreases haem availability for NOS2 synthesis. NOS2 inhibition may explain the antinflammatory effects of HmOx induction which could also be used therapeutically in situations when NO hyperproduction leads to cytotoxic effects such as inflammation or transplant rejection.

Animals↗
PubMed1994

Enhanced vascular permeability in solid tumor is mediated by nitric oxide and inhibited by both new nitric oxide scavenger and nitric oxide synthase inhibitor.

A newly discovered nitric oxide radical scavenger, an imidazolineoxyl N-oxide derivative, was used to investigate the role of nitric oxide radical (.NO) in the vascular permeability enhancement of solid tumor. Sarcoma-180 solid tumor in ddY mice was used for this experiment. Electron spin resonance spectroscopy was used to quantitate the reacted and unreacted scavenger. The results showed that extensive extravasation, assessed by intravenous injection of Evans blue, could be greatly suppressed by both .NO scavenger administered orally and .NO synthase inhibitor administrated intraperitoneally. This indicates that .NO is responsible for the vascular permeability in solid tumors.

Amino Acid Oxidoreductases↗
PubMedDate not supplied

Small-angle X-ray scattering study of the interaction of poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) triblock copolymers with lipid bilayers.

The relationship between molecular architecture and the nature of interactions with lipid bilayers has been studied for a series of poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymers using small-angle X-ray scattering (SAXS) and thermal analysis (differential scanning calorimetry, DSC). The number of molecular repeat units in the hydrophobic poly(propylene oxide), PPO, block has been found to be a critical determinant of the nature of triblock copolymer-lipid bilayer association. For dimyristoyl-sn-glycero-3-phosphocholine (DMPC)-based biomembrane structures, polymers possessing a PPO chain length commensurate with the acyl chain dimensions of the lipid bilayer yield highly ordered, swollen lamellar structures consistent with well-integrated (into the lipid bilayer) PPO blocks. Triblock copolymers of lesser PPO chain length yield materials with structural characteristics similar to a simple dispersion of DMPC in water. Increasing the concentration (from 4 to 12 mol %) of well-integrated triblock copolymers enhances the structural ordering of the lamellar phase, while concentrations exceeding 16 mol % result in the formation of a hexagonal phase. Examination of temperature-induced changes in the structure of these mesophases (complex fluids) reveals that if the temperature is reduced sufficiently, all compositions exclude polymer and thus exhibit the characteristic SAXS pattern for hydrated DMPC bilayers. Increasing the temperature promotes better insertion of the polymers possessing PPO chain lengths sufficient for membrane insertion. No temperature-induced structural changes are observed in compositions prepared with PEO-PPO-PEO polymers that feature PPO length insufficient to permit full incorporation into the lipid bilayer.

Biocompatible Materials↗