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PubMed1976

Generators and topography of hippocampal theta (RSA) in the anaesthetized and freely moving rat.

Spontaneous and hypothalamically induced hippocampal rhythmical slow activity (RSA or theta) was studied acutely in rats anaesthetized with urethane or immobilized with D-tubocurarine. Systematic tracking of microelectrodes showed two foci of hippocampal RSA, one located in the basal part (stratum oriens) of CAl (mean amplitude 1 mV) and the other located in stratum moleculare of the dorsal blade of the fascia dentata (mean amplitude 2 mV). The hippocampal RSA recorded from the lower blade of the fascia dentata was always smaller than that found in the upper blade (mean amplitude 1 mV). The whole dorsal hippocampal extent within each generator zone was shown to be in synchrony, and the respective generator zones of both hippocampi were synchronous with one another. A null zone in stratum radiation was found interposed between the two generators and a zone of large amplitude fast activity (30-50 Hz) was localized to the hilus of the fascia dentata. Wave form analysis showed that the RSA recorded from the two generators was approximately 180 degrees out of phase. Amplitude and analysis of phase changes of RSA recorded in brain areas outside of the two generator zones suggested that such activity was due to physical spread from the two generators, with the possible exception of a restricted portion of CA3. The existence of the two generators, 180 degrees out of phase, was demonstrated in freely moving rats. Behavioural observations showed that the two generators were related systematically to concurrent motor behaviour. Preliminary observations suggest that, of the two generators, the one located in CAl may be the more variable.

Animals↗

PubMed1979

Hippocampal theta in rats under urethane: generators and phase relations.

Recordings were made from the directly visualized dorsal hippocampus of urethane-anesthetized rats with silver ball and tungsten microelectrodes. Theta of about 5 c/sec was elicited by reticular stimulation and was located in two broad strata in and subjacent to CA1. A superficial generator yielded 200-250 microV theta from the alveus, stratum oriens and stratum pyramidale; a null-theta and phase-reversal point was located in stratum radiatum; a deep generator yielded 300-500 microV theta in stratum lacunosum-moleculare of the hippocampus and distal stratum moleculare of the dentate gyrus, with maximum amplitude near the fissure. No theta was found in CA3. Cross-correlation analyses between generators yielded coefficients on the order of -0.80 while within a generator--especially the deep one--coefficients could reach +0.95. Phase analyses showed the two generators were about 180 degrees out of phase, with the deep generator leading. Septotemporal movement along the upper generator yielded no phase shifts; similar movement along the deep generator showed slight lead ing in septal portions. Subiculofimbrial movement in both generators showed a complex pattern of phase shifts: generally, subicular sites led fimbrial sites, but an inversion of 10 degrees-20 degrees occurred in the millimeter anterior to the center of the hippocampus. Anatomical, phase and other datal led to consideration of a possible retrohippocampal role in supplementing the well-known pacemaker in the medial septum.

Anesthesia, General↗

PubMed1995

Generation of hydroperoxides in isolated rat hepatocytes and hepatic mitochondria exposed to hydrophobic bile acids.

BACKGROUND & AIMS: The mechanisms causing liver injury in cholestatic diseases are unclear. The hypothesis that accumulation of hydrophobic bile acids in hepatocytes during cholestasis leads to generation of oxygen free radicals and oxidative injury was tested. The aim of this study was to determine if hydrophobic bile acid toxicity is associated with increased hydroperoxide generation in isolated rat hepatocytes and mitochondria. METHODS: Hepatocytes were exposed to taurochenodeoxycholic acid (TCDC; 0-2000 mumol/L) or taurocholic acid (TC; 1000 mumol/L), and cellular injury, intracellular hydroperoxide generation, and thiobarbituric acid-reacting substances (TBARS) were measured. Isolated mitochondria were incubated with 400 mumol/L chenodeoxycholic acid or 400 mumol/L cholic acid, and hydroperoxide generation was measured fluorometrically. RESULTS: Hepatocyte injury, hydroperoxide generation, and TBARS increased over 4 hours on exposure to TCDC but not TC. Hydroperoxide generation preceded hepatocyte injury and accumulation of TBARS. Preincubation of hepatocytes with the antioxidant, d-alpha-tocopheryl succinate, completely abrogated cellular injury, hydroperoxide, and TBARS generation. Hydroperoxide generation was increased in mitochondria exposed to chenodeoxycholic acid. CONCLUSIONS: Intracellular generation of hydroperoxides by mitochondria appears to be an early event in hydrophobic bile acid-induced hepatocyte toxicity. Antioxidants may be of benefit in cholestasis.

Animals↗

PubMed1989

The spike generating mechanism of cat retinal ganglion cells.

The spike generating mechanism (SGM) of sustained and transient-type ganglion cells has been investigated from intracellular recordings in the cat retina. The relationship between the generator potential and the impulse pattern, which are respectively the input and the output of the SGM, has been studied after separating one component from the other. Comparison of averaged generator potentials and the corresponding PSTHs showed that the spike generator is highly sensitive to changes of the generator potential. It proved to be relatively indifferent to the prevailing average levels of depolarization. During sustained parts of the responses the SGM exhibits a stochastic nature. At higher light flicker frequencies, during spike bursts, on the other hand spike generation is very regular and phase locked to the stimulus. The averaged generator potentials were also used to develop and test a set of minimal, computer simulated models of the spike generator. A slow threshold adaptation (time constant about 50 msec) is absolutely necessary in addition to the faster refractory recovery in order to produce spike patterns similar to those measured during the corresponding response periods. The developed model accounts completely for the observed characteristics of ganglion cell spike generation under a wide variety of light stimulus regimes and both for the sustained and for the transient type of ganglion cell.

Action Potentials↗

PubMed1990

The inhibition of intrinsic prothrombinase and its generation by heparin and four derivatives in prothrombin poor plasma.

The effect of different heparins and a synthetic pentasaccharide on the inhibition of intrinsic prothrombinase and of its generation was studied by a new technique, using a defibrinated prothrombin poor human plasma, supplemented with phospholipids and calcium. Prothrombinase activity was evaluated on purified prothrombin with a chromogenic substrate. This technique is designed to bypass the interference of massive endogenous thrombin generation on the measurement of prothrombinase activity. We first validated the specificity of the technique by using specific Xa and IIa inhibitors. Then, the inhibition of prothrombinase generation and the inhibition of generated prothrombinase were both studied. The results showed that anti-Xa activity measured on exogenous bovine factor Xa added to plasma was not correlated with the inhibition of prothrombinase generation or prothrombinase activity. The concentrations required for unfractionated heparin (the 4th International Standard: 4th IS UH), 1st International Standard Low Molecular Weight Heparins (1st IS LMWH), enoxaparin, Fraxiparine, and pentasaccharide in order to inhibit preformed prothrombinase were significantly higher than those necessary to inhibit prothrombinase generation. These data suggest that anti-Xa activity of unfractionated heparin and its derivatives does not completely reflect the extent of the inhibition of intrinsic prothrombinase generation by UH, LMWH, and pentasaccharide. On the other hand, anti-IIa activity of heparins could be responsible for the inhibition of prothrombinase generation. The action of pentasaccharide devoid of anti-IIa activity on prothrombinase generation appears related to its indirect effect on the formation of initial thrombin traces. This new technique provides a tool to study the essential role played by thrombin during the early steps of coagulation.

Factor Xa Inhibitors↗

PubMed1993

Generation of free radicals in reactions of Ni(II)-thiol complexes with molecular oxygen and model lipid hydroperoxides.

The generation of free radicals from reactions of nickel(II)-thiol complexes with molecular oxygen and model lipid hydroperoxides was investigated by electron spin resonance (ESR) utilizing 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as a spin trap. Incubation of nickel(II) [Ni(II)] with cysteine in an aerobic environment generated hydroxyl (.OH) radical, which then reacted with cysteine to generate a carbon-centered alkyl (.R) radical. Radical generation was inhibited under a nitrogen atmosphere. Model lipid hydroperoxides, cumene hydroperoxide, and t-butyl hydroperoxide enhanced the yield of these radicals and also generated an alkoxyl (.OR) radical. Radical yield decreased by approximately half under a nitrogen atmosphere. Although histidine did not cause radical formation in the reaction between Ni(II) and cumene hydroperoxide under aerobic conditions, the addition of histidine to a mixture containing Ni(II), cysteine, and cumene hydroperoxide under the same experimental conditions increased the yield of .R radical but lowered the yield of .OR and .OH radical adducts. It thus appears that histidine caused the .OH attack to be more site-specific. Similar results were obtained utilizing t-butyl hydroperoxide. Penicillamine or N-acetylcysteine yielded similar results except that under aerobic conditions, reaction between Ni(II) and N-acetylcysteine without hydroperoxide did not generate a significant concentration of free radicals. Under the same experimental conditions, cystine did not generate any detectable free radicals, suggesting an important role of the -SH group in Ni(II)-mediated free radical generation. The results indicate that free radical generation from the reaction of Ni(II)-thiol complexes and molecular oxygen, and/or lipid hydroperoxides, may play an important role in the mechanism(s) of Ni(II) toxicity and carcinogenesis.

Acetylcysteine↗

PubMed1990

Three-generation reproduction study with dioctyl sodium sulfosuccinate in rats.

Groups of 30 male and 30 female rats (F0) were fed diets containing 0, 0.1, 0.5, or 1.0% dioctyl sodium sulfosuccinate (DSS) for 10 and 2 weeks, respectively. The F0 animals were then mated to produce an F1 litter. Groups of 30 male and 30 female F1 animals were fed the same dose levels for at least 10 weeks postweaning, and the breeding program was repeated to produce F2 animals. F3 animals were produced from F2 animals by the same procedure. The study was terminated with the F3 weanlings. Test diets were fed continuously throughout the study. All F0, F1, and F2 adults and F3 weanlings (one/sex/litter) were necropsied and given a macroscopic examination. There were no effects on reproductive function for parental animals of either sex during any of the three generations in this study. At the highest dose level (1.0% DSS), body weights were lower than those of controls during the premating phase for males in all three generations and for F1 and F2 females. Body weights for F1 and F2 males and females in the 0.5% dose group were also low during the premating phase. Pup weights on Lactation Day 0 were significantly lower than those of controls only for the high-dose group during the third generation. However, lower pup weight gains in the mid- and high-dose groups resulted in significantly lower pup weights on Day 21 for all three generations. Perinatal pup survival across three generations ranged from 96 to 100% for the control and treated groups. Pup survival ranged from 95 to 100% for controls, from 98 to 100% for low- and mid-dose groups, and from 91 to 99% for the high-dose group. There were no treatment-related mortality and antemortem or macroscopic observations. In summary, DSS administered in the diet to three successive generations of rats at levels of 0.5 and 1.0% caused a reduction in body weights for parental males in all generations and for F1 and F2 females. Pup weights at the 0.5 and 1.0% dose levels were also lower than those of the control in all three generations. However, the reduced body weights did not interfere with development of normal reproductive performance. DSS at levels up to 1.0% had no effects on the reproductive function of either sex in any generation and produced no treatment-related antemortem or macroscopic observations.

Animals↗

PubMed1994

Direct detection of radical generation in rat liver nuclei on treatment with tumour-promoting hydroperoxides and related compounds.

EPR spin trapping has been employed to directly detect radical production in isolated rat liver nuclei on exposure to a variety of hydroperoxides and related compounds which are known, or suspect, tumour promoters. The hydroperoxides, in the absence of reducing equivalents, undergo oxidative cleavage, generating peroxyl radicals. In the presence of NADPH (and to a lesser extent NADH) reductive cleavage of the O-O bond generates alkoxyl radicals. These radicals undergo subsequent rearrangements and reactions (dependent on the structure of the alkoxyl radical), generating carbon-centred radicals. Acyl peroxides and peracids appear to undergo only reductive cleavage of the O-O bond. With peracids this cleavage can generate aryl carboxyl (RCO2.) or hydroxyl radicals (HO.); with acyl peroxides, aryl carboxyl radicals are formed and, in the case of t-butyl peroxybenzoate, alkoxyl radicals (RO.). The radicals detected with each peroxide are similar in type to those detected in the rat liver microsomal fraction, although the extent of radical production is lower. The subsequent reactions of the initially generated radicals are similar to those determined in homogeneous chemical systems, suggesting that they are in free solution. Experiments with NADPH/NADH, heat denaturation of the nuclei and various inhibitors suggest that radical generation is an enzymatic process catalysed by haemoproteins, in particular cytochrome P-450, and that NADPH/cytochrome P-450 reductase is involved in the reductive cleavage of the O-O bond. The generation of these radicals by the rat liver nuclear fraction is potentially highly damaging for the cell due to the proximity of the generating source to DNA. Several previous studies have shown that some of the radicals detected in this study, such as aryl carboxyl and aryl radicals, can damage DNA, via various reactions which result in the generation of strand breaks and adducts to DNA bases: these processes are suggested to play an important role in the tumour promoting activity of these hydroperoxides and related compounds.

Animals↗

PubMed2006

Group V secretory phospholipase A2 amplifies the induction of cyclooxygenase 2 and delayed prostaglandin D2 generation in mouse bone marrow culture-derived mast cells in a strain-dependent manner.

Activation of mouse bone marrow-derived mast cells (BMMC) with stem cell factor (SCF) or IgE and antigen elicits exocytosis and an immediate phase of prostaglandin (PG) D(2) and leukotriene (LT) C(4) generation. Activation of BMMC by SCF, IL-1beta and IL-10 elicits a delayed phase of PGD(2) generation dependent on cyclooxygenase (COX) 2 induction. Cytosolic phospholipase A(2) alpha provides arachidonic acid in both phases and amplifies COX-2 induction. Pharmacological experiments implicate an amplifying role for secretory (s) PLA(2). We used mice lacking the gene encoding group V sPLA(2) (Pla2g5-/-) to definitively test its role in eicosanoid generation by BMMC. Pla2g5-/- BMMC on a C57BL/6 genetic background showed a modest reduction in exocytosis and immediate PGD(2) generation after activation with SCF or with IgE and antigen, while LTC(4) generation was not modified. Delayed-phase PGD(2) generation and COX-2 induction were reduced approximately 35% in C57BL/6 Pla2g5-/- BMMC and were restored by exogenous PGE(2). There was no deficit in either phase of eicosanoid generation by Pla2g5-/- BMMC on a BALB/c background. Thus, group V sPLA(2) amplifies COX-2 expression and delayed phase PGD(2) generation in a strain-dependent manner; it has at best a limited role in immediate eicosanoid generation by BMMC.

Animals↗

PubMed2006

Ex vivo rapamycin generates Th1/Tc1 or Th2/Tc2 Effector T cells with enhanced in vivo function and differential sensitivity to post-transplant rapamycin therapy.

Rapamycin prevention of murine graft-versus-host disease (GVHD) is associated with a shift toward Th2- and Tc2-type cytokines. Recently, we found that use of rapamycin during ex vivo donor Th2 cell generation enhances the ability of adoptively transferred Th2 cells to prevent murine GVHD. In this study, using a method, without antigen-presenting cells, of T-cell expansion based on CD3,CD28 costimulation, we evaluated whether (1) rapamycin preferentially promotes the generation of Th2/Tc2 cells relative to Th1/Tc1 cells, (2) rapamycin-generated T-cell subsets induce cytokine skewing after allogeneic bone marrow transplantation (BMT), and (3) such in vivo cytokine skewing is sensitive to post-BMT rapamycin therapy. Contrary to our hypothesis, rapamycin did not preferentially promote Th2/Tc2 cell polarity, because rapamycin-generated Th1/Tc1 cells secreted type I cytokines (interleukin [IL]-2 and interferon-gamma) did not secrete type II cytokines (IL-4, IL-5, IL-10, or IL-13) and mediated fasL-based cytolysis. Rapamycin influenced T-cell differentiation, because each of the Th1, Th2, Tc1, and Tc2 subsets generated in rapamycin had increased expression of the central-memory T-cell marker, L-selectin (CD62L). Rapamycin-generated Th1/Tc1 and Th2/Tc2 cells were not anergic but instead had increased expansion after costimulation in vitro, increased expansion in vivo after BMT, and maintained full capacity to skew toward type I or II cytokines after BMT, respectively; further, rapamycin-generated Th1/Tc1 cells mediated increased lethal GVHD relative to control Th1/Tc1 cells. Rapamycin therapy after BMT in recipients of rapamycin-generated Th1/Tc1 cells greatly reduced Th1/Tc1 cell number, greatly reduced type I cytokines, and reduced lethal GVHD; in marked contrast, rapamycin therapy in recipients of rapamycin-generated Th2/Tc2 cells nominally influenced the number of Th2/Tc2 cells in vivo and did not abrogate post-BMT type II cytokine skewing. In conclusion, ex vivo and in vivo usage of rapamycin may be used to modulate the post-BMT balance of Th1/Tc1 and Th2/Tc2 cell subsets.

Animals↗

PubMed2005

Different neuronal pathways support the generation of general and specific mental images.

The aim of this functional magnetic resonance imaging (fMRI) study was to investigate the neural correlates associated with the generation of general (i.e., prototypical) and specific (i.e., exemplar) visual mental images from concrete nouns. The fMRI paradigm included a non-imagery baseline, and two activation conditions requiring the generation of either general or specific images. Image generation times and brain activation were recorded. Analysis of the behavioral results showed that generating general images took less than the specific ones. The comparison of each activation condition with the baseline showed significant increase in brain activation in left frontal areas in both kinds of images, with the additional involvement of the posterior cingulate cortex during the generation of specific images. When the two activation conditions were contrasted with each other and masked for their respective comparison with baseline, significant activation was found in right frontal areas for general mental images, whereas a significant increase in activation in the left superior frontal region and the right thalamus was detected during the generation of specific mental images. These findings suggest that general and specific mental images are generated with the support of two different neural pathways. The generation of general images seems to involve brain areas associated with the formation of global gestalt-like images (areas in the right hemisphere), while the generation of specific mental images appears to require additional support from areas involved in the retrieval of visual details (i.e., the right thalamus).

Adult↗

PubMed2006

Dynamic aphasia in progressive supranuclear palsy: a deficit in generating a fluent sequence of novel thought.

We report a patient (KAS) who presented with pure dynamic aphasia in the context of progressive supranuclear palsy (PSP). KAS had the hallmark propositional language impairment in the context of preserved naming, reading, repetition and comprehension skills. The severity of KAS's propositional language deficit was demonstrated to be comparable to other dynamic aphasic patients. Remarkably, despite virtually abolished propositional speech, KAS was unimpaired on word and sentence level generation tasks that required a single response. This dissociation was further investigated on two discourse level generation tasks that required the generation of multiple connected sentences. Quantitative production analysis and novelty measures demonstrated that her performance was extremely reduced and characterised by a lack of novel words and sentences and a tendency to perseverate. This pattern of performance suggests that there may be two subtypes of dynamic aphasia. Patients with the more documented first subtype have language-specific deficits, fail word and sentence level generation tests and have left inferior frontal gyrus lesions. Patients with the second subtype, like KAS, pass word and sentence level generation tests and fail discourse level generation tests. They have a verbal and non-verbal generation deficit and bilateral frontal and subcortical damage. Our findings are discussed with reference to executive functioning accounts of dynamic aphasia and models of speech production. We interpret our patients' impairment as being underpinned by a deficit in one set of mechanisms involved in discourse generation; namely the generation of a fluent sequence of novel thought.

Aphasia↗

PubMed2005

Attachment of Acanthamoeba to first- and second-generation silicone hydrogel contact lenses.

PURPOSE: To investigate the attachment of Acanthamoeba to first- and second-generation silicone hydrogel contact lenses, and to determine if patient wear or the presence of a bacterial biofilm coating affects attachment characteristics. DESIGN: Experimental study. PARTICIPANTS AND CONTROLS: Attachment to the silicone hydrogel lenses was compared with that to a conventional hydrogel control lens. Sixteen replicates (n = 16) were carried out for unworn, worn, and biofilm-coated lenses of each type. METHODS: Unworn, worn, and Pseudomonas aeruginosa biofilm-coated first-generation (lotrafilcon A) and second-generation (galyfilcon A) silicone hydrogel and conventional hydrogel (etafilcon A) lens quarters were incubated for 90 minutes in suspensions of plate-cultured Acanthamoeba castellanii trophozoites. MAIN OUTCOME MEASURES: Trophozoites attached to one surface of each lens quarter were counted by direct light microscopy. Logarithmic transformation of data allowed the use of parametric analysis of variance for statistical analysis. RESULTS: Attachment of Acanthamoeba was affected significantly by lens material type (P<0.001), with higher numbers of trophozoites attaching to the first-generation lotrafilcon A silicone hydrogel lens, compared with the second-generation galyfilcon A lens and the conventional hydrogel lens. Attachments to the latter 2 lenses did not differ significantly from each other (P = 0.126). Patient wear and the presence of a bacterial biofilm had no significant effect on attachment to the lotrafilcon A lens (P = 0.426) but did significantly increase attachment to the galyfilcon A (P<0.001) and the etafilcon A (P = 0.009) lenses; attachment to the latter 2 lenses was still significantly less than that found with the first-generation silicone hydrogel (P<0.001). CONCLUSIONS: Acanthamoeba demonstrated a significantly greater affinity for the first-generation silicone hydrogel lens as compared with the second-generation silicone hydrogel and the conventional hydrogel. If exposed to Acanthamoeba (e.g., when showering or swimming, through noncontinuous wear and ineffective lens care regimes), first-generation silicone hydrogel lenses may promote a greater risk of Acanthamoeba infection due to the enhanced attachment characteristics of this lens material. However, prospective studies in patients are required to determine if these experimental results are clinically significant.

Acanthamoeba castellanii↗

PubMed1998

Cobalt-mediated generation of reactive oxygen species and its possible mechanism.

Electron spin resonance spin trapping was utilized to investigate free radical generation from cobalt (Co) mediated reactions using 5,5-dimethyl-1-pyrroline (DMPO) as a spin trap. A mixture of Co with water in the presence of DMPO generated 5,5-dimethylpyrroline-(2)-oxy(1) DMPOX, indicating the production of strong oxidants. Addition of superoxide dismutase (SOD) to the mixture produced hydroxyl radical (.OH). Catalase eliminated the generation of this radical and metal chelators, such as desferoxamine, diethylenetriaminepentaacetic acid or 1,10-phenanthroline, decreased it. Addition of Fe(II) resulted in a several fold increase in the .OH generation. UV and O2 consumption measurements showed that the reaction of Co with water consumed molecular oxygen and generated Co(II). Since reaction of Co(II) with H2O2 did not generate any significant amount of .OH radicals, a Co(I) mediated Fenton-like reaction [Co(I) + H2O2-->Co(II) + .OH + OH-] seems responsible for .OH generation. H2O2 is produced from O2.- via dismutation, O2.- is produced by one-electron reduction of molecular oxygen catalyzed by Co. Chelation of Co(II) by biological chelators, such as glutathione or beta-ananyl-3-methyl-L-histidine alters, its oxidation-reduction potential and makes Co(II) capable of generating .OH via a Co(II)-mediated Fenton-like reaction [Co(II) + H2O2-->Co(III) + .OH + OH-]. Thus, the reaction of Co with water, especially in the presence of biological chelators, glutathione, glycylglycylhistidine and beta-ananyl-3-methyl-L-histidine, is capable of generating a whole spectrum of reactive oxygen species, which may be responsible for Co-induced cell injury.

Catalase↗

PubMed1999

Generation of acetate and production of ethyl-lysine in the reaction of acetaldehyde plus serum albumin.

We report that incubation of acetaldehyde with bovine serum albumin results in the generation of acetate in a reaction that is directly proportional to the levels of albumin and exponentially dependent on the concentration of acetaldehyde. Both reactants need to be present for acetate to be formed. The oxidation of acetaldehyde into acetate requires that a reduced product also be generated in the reaction. It was hypothesized that, at high concentrations, acetaldehyde itself may reduce the Schiff bases formed in the reaction of a second molecule of acetaldehyde with amino groups in the protein, resulting in the generation of ethyl-lysine moieties. Incubation of acetaldehyde (240 mM) with bovine serum albumin was found to generate ethyl-lysine moieties as determined by a specific monoclonal antibody. Immunization of rabbits with products of the reaction of bovine serum albumin with acetaldehyde led to the generation of antibodies that reacted to reduced adducts formed in the reaction of acetaldehyde and proteins in the presence of sodium cyanoborohydride. However, the generation of acetate from acetaldehyde plus albumin was 60-fold greater than could be explained by the reduction of Schiff bases, as determined by the maximal incorporation of [14C]-acetaldehyde into an acid-precipitable protein fraction. Thus, other mechanisms to generate acetate also occur. The present findings provide an explanation for earlier reports that acetaldehyde adducts formed under "nonreducing" conditions generate antibodies that recognize reduced acetaldehyde protein adducts. However, the mechanism by which the bulk of acetate is generated in the reaction of acetaldehyde and bovine serum albumin remains to be elucidated.

Acetaldehyde↗

PubMed1986

Stimuli-induced superoxide radical generation in vitro by human alveolar macrophages from smokers: modulation by N-acetylcysteine treatment in vivo.

Bronchoalveolar lavage (BAL) was performed on nine healthy nonsmoking subjects and on 11 healthy smokers; in the last mentioned group lavage was performed before and after eight weeks treatment with N-acetylcysteine (NAC; 200 mg t.i.d.). The BAL cells were cultured for 2 h or overnight. Adherent cells were examined for their capacity to generate superoxide radicals (determined by superoxide dismutase (SOD)-inhibitable cytochrome C-reduction) at stimulation with phorbol 12-myristate 13-acetate (PMA), serum-treated zymosan (STZ), the calcium ionophore A23187, or the chemotactic tripeptide formyl-methionylleucylphenylalanine (FMLP). Cells from nonsmokers responded with a very low degree of O(2)-generation to any of the stimuli employed whether cultured for 2 h or overnight. Cells from smokers also responded with low O(2)-generation after 2 h of culture. However, cells from smokers cultured overnight responded with marked O(2)-generation to PMA and STZ but the responses to FMLP and A23187 were low. NAC-treatment of the smokers resulted in a reduced degree of both PMA- and STZ-induced O(2)-generation in five individuals. In two other subjects, PMA-induced (but not STZ-induced) O(2)-generation was reduced. Two individuals showed increased O(2)-generation to PMA- and to STZ-stimulation after NAC-treatment. Mean values of O(2)-generation induced by A23187 or by FMLP were significantly reduced for cells harvested after NAC-treatment. Mean values for PMA-induced O(2)-generation also tended to be reduced by the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcysteine↗

PubMed2002

Inhibition of superoxide generation from neuronal nitric oxide synthase by heat shock protein 90: implications in NOS regulation.

Besides NO, neuronal NO synthase (nNOS) also produces superoxide (O(2)(-.) at low levels of L-arginine. Recently, heat shock protein 90 (hsp90) was shown to facilitate NO synthesis from eNOS and nNOS. However, the effect of hsp90 on the O(2)(-.) generation from NOS has not been determined yet. The interrelationship between its effects on O(2)(-.) and NO generation from NOS is also unclear. Therefore, we performed electron paramagnetic resonance measurements of O(2)(-.) generation from nNOS to study the effect of hsp90. Purified rat nNOS generated strong O(2)(-.) signals in the absence of L-arginine. In contrast to its effect on NO synthesis, hsp90 dose-dependently inhibited O(2)(-.) generation from nNOS with an IC(50) of 658 nM. This inhibition was not due to O(2)(-.) scavenging because hsp90 did not affect the O(2)(-.) generated by xanthine oxidase. At lower levels of L-arginine where marked O(2)(-.) generation occurred, hsp90 caused a more dramatic enhancement of NO synthesis from nNOS as compared to that under normal L-arginine. Significant O(2)(-.) production was detected from nNOS even at intracellular levels of L-arginine. Adding hsp90 prevented this O(2)(-.) production, leading to enhanced nNOS activity. Thus, these results demonstrated that hsp90 directly inhibited O(2)(-.) generation from nNOS. Inhibition of O(2)(-.) generation may be an important mechanism by which hsp90 enhances NO synthesis from NOS.

Animals↗

PubMed2002

Nitric oxide mediated modulation of free radical generation response in the rat polymorphonuclear leukocytes: a flowcytometric study.

Nitric oxide (NO) synthesis and free radical generation from polymorphonuclear leukocytes (PMNs) play an important role in several pathological conditions. It is therefore important to understand the regulatory mechanisms of free radical generation from PMNs. Flowcytometry can be used to assess generation of reactive oxygen and nitrogen species from PMNs by using fluorescent probes. In the present study regulation of NO synthesis in the control and lipopolysaccharide (LPS) treated rat PMNs has been investigated. Free radical generation was assessed by flow cytometry using a dye, 2'7'-dichlorodihydrofluorescein diacetate (DCFDA), dihydrorhodamine-123 (DHR) and 4,5-diaminofluorescein diacetate (DAF). Superoxide dismutase (SOD), and catalase significantly attenuated the arachidonic acid (AA, 1 x 10(-6) M) induced free radical generation, while 4-aminobenzoicacid hydrazide (ABH), myeloperoxidase (MPO) inhibitor had no significant effect. Intracellular and extracellular calcium levels also modulated FR generation. AA induced free radical generation from PMNs was also enhanced significantly after LPS treatment. NO synthase (NOS) inhibitors, aminoguanidine (AG) and 7-nitroindazole (NI) inhibited arachidonic acid induced free radical generation from LPS treated PMNs, while in control PMNs NOS inhibition had no effect. Augmentation of free radical generation from rat PMNs following LPS treatment seems to be regulated by NO.

Animals↗