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PubMed2001

Endocrine-regulated and protein kinase C-dependent generation of superoxide by rat preovulatory follicles.

The ovulatory LH surge results in follicular inflammation with an increase in cytokines and PGs. Reactive oxygen species (ROS) are also produced during inflammatory processes. To study ROS generation during the ovulatory cascade, preovulatory follicles were dissected from immature female rats primed with PMSG. Follicles were isolated, and ROS generation was assessed by luminol-amplified chemiluminescence. Immature rat granulosa cells were also subjected to luminometry after isolation from immature rats treated with diethylstilbestrol. Phorbol ester-stimulated ROS generation by follicular cells was completely suppressed by superoxide dismutase and the NADPH/NADH oxidase inhibitor diphenylene iodonium bisulfate, whereas catalase was without effect. Fractionation of granulosa cells with an antibody against leukocyte common antigen-1 showed that leukocyte-enriched cells produced more than 95% of the superoxide measured. In vivo treatment with LH produced a 5-fold increase in phorbol-stimulated superoxide production by isolated follicles. This response was maximal within 4 h and was blocked by indomethacin. In vivo administration of PGE(2) and PGF(2alpha) did not reverse the blockade by indomethacin; however, isolated follicles incubated with PGE(2) produced a time-dependent increase in phorbol-stimulated superoxide generation. Thus, a superoxide generator is present in the preovulatory follicle that is leukocytic in origin, hormone regulated, and activated by a protein kinase C-dependent pathway. The regulated generation of superoxide by preovulatory follicles may indicate a role for ROS in the periovulatory period.

Animals↗
PubMed2004

Trans-activation of mutant follicle-stimulating hormone receptors selectively generates only one of two hormone signals.

Previously, we reported that a liganded LH receptor (LHR) is capable of activating itself (cis-activation) and other nonliganded LHRs to induce cAMP (trans-activation). Trans-activation of the LHR raises two crucial questions. Is trans-activation unique to LHR or common to other G protein-coupled receptors? Does trans-activation stimulate phospholipase Cbeta as it does adenylyl cyclase? To address these questions, two types of novel FSH receptors (FSHRs) were constructed, one defective in hormone binding and the other defective in signal generation. The FSHR, a G protein-coupled receptor, comprises two major domains, the N-terminal extracellular exodomain that binds the hormone and the membrane-associated endodomain that generates the hormone signals. For signal defective receptors, the exodomain was attached to glycosyl phosphatidylinositol (ExoGPI) or the transmembrane domain of CD8 immune receptor (ExoCD). ExoGPI and ExoCD can trans-activate another nonliganded FSH. Surprisingly, the trans-activation generates a signal to activate either adenylyl cyclase or phospholipase Cbeta, but not both. These results indicate that trans-activation in these mutant receptors is selective and limited in signal generation, thus providing new approaches to investigating the generation of different hormone signals and a novel means to selectively generate a particular hormone signal. Our data also suggest that the FSHR's exodomain could not trans-activate LHR.

Adenylyl Cyclases↗
PubMed1999

Inhibition by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) of responses to nitric oxide-donors in rat pulmonary artery: influence of the mechanism of nitric oxide generation.

ODQ, (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, an inhibitor of soluble guanylate cyclase) inhibits vasorelaxant responses to nitric oxide (NO)-donor drugs, but the extent of the inhibition varies depending on the NO donor studied. The purpose of this study was to test the hypothesis that these variations in the effects of ODQ reflect differences in the mechanisms whereby each NO donor generates NO. On pulmonary artery preparations pre-contracted submaximally with phenylephrine, ODQ (3 microM) almost abolished the relaxant responses to glyceryl trinitrate, isosorbide dinitrate and nitroprusside; each of these drugs requires activation in the tissue (by enzymes or reducing agents) to generate NO. In contrast, ODQ (3 microM) caused a parallel shift in the concentration-relaxation curves to linsidomine (SIN-1), FK409, MAHMA NONOate and spermine NONOate (1.63 to 2.54 log units) with no depression in maximum response; each of these NO donors generates NO in the physiological bathing solution without requiring tissue activation. For the four drugs in this group, the effects of 10 microM ODQ were not significantly greater than the effects of 3 microM ODQ; thus there was an ODQ-resistant component to the response suggesting that part of the response involved a mechanism that was independent of soluble guanylate cyclase. NO donors that require tissue activation probably generate NO within the smooth-muscle cell, whereas those that do not require tissue activation generate NO outside the cell. Hence it is concluded that the site of NO generation (intra- or extracellular) might determine whether or not there is an ODQ-resistant component in the relaxation response.

Animals↗
PubMed1985

Serotonin modulates the central pattern generator for locomotion in the isolated lamprey spinal cord.

The central pattern generator for locomotion in the spinal cord of the lamprey can be activated in vitro by the addition of D-glutamate to the bathing saline. Serotonin has no effects when bath-applied alone, but it modulates the D-glutamate-activated swimming pattern. Three major effects are observed: a dose-dependent reduction in the frequency of rhythmic ventral root burst discharge; enhancement of the intensity of burst discharge, due in part to the recruitment of previously inactive motoneurones; prolongation of the intersegmental phase lag. Motoneurone activation appears to result from enhanced synaptic drive from the central pattern generator; no direct effects of serotonin on the motoneurones themselves (resting potential, input resistance or threshold for action potential generation) were observed. Theoretical and experimental studies suggest that the prolongation of the intersegmental phase lag results at least in part from differential effects of serotonin on segmental oscillators in different parts of the spinal cord. Isolated caudal pieces of the cord were more strongly affected by serotonin than isolated rostral pieces. We propose that serotonin may be an endogenous modulator of the central pattern generator for locomotion in the lamprey. It may have a role in the generation of a family of related undulatory movements (swimming, crawling, burrowing) by a single central pattern generator.

Animals↗
PubMed1996

Molecular forces involved in force generation during skeletal muscle contraction.

Recent advances in protein chemistry and the kinetic analysis of tension transients in skeletal muscle fibres have enabled us to elucidate the molecular forces involved in force generation by cross-bridges. On the basis of the temperature effect, we conclude that the elementary step that generates force is an endothermic reaction (the enthalpy change delta H degree = 124 kJ mol-1 at 15 degrees C), which accompanies a large entropy increase (delta S degree = 430JK-1 mol-1) and a reduction in the heat capacity (delta C p = -6.4kJ K-1 mol-1). Thus, it can be concluded that the force-generating step is an entropy-driven reaction. The above results suggest that hydrophobic interactions are the primary cause of force generation, and that polar interactions (hydrogen bonding and charge interactions) are involved to a lesser degree. On the basis of the thermodynamic data, we estimate that during force generation approximately 50 nm2 of surface area is involved for hydrophobic interactions and another 30 nm2 for polar interactions. These data suggest that both the actomyosin interaction and the cleft closure of the myosin head are essential for force generation.

Actins↗
PubMed2004

Superoxide generation by Nox1 in guinea pig gastric mucosal cells involves a component with p67(phox)-ability.

Nox1, a homologue of gp91(phox) subunit of the phagocyte NADPH oxidase, is responsible for spontaneous superoxide (O(2)(-)) generation in guinea pig gastric mucosal cells (GMC), but involvement of regulatory components (p67(phox), p47(phox), and Rac) which are essential in phagocytes remains unknown. Here, we aimed to figure out how Nox1 of GMC achieves an active oxidase status. GMC in primary culture show low O(2)(-) generation but acquire a 9-fold higher activity when cultured with Helicobacter pylori lipopolysaccharide (LPS), in correlation with a far increased Nox1 expression. Investigation into the O(2)(-)-generating ability of LPS-induced Nox1 in cell-free reconstitution assays showed that: 1) Nox1 is unable to generate O(2)(-) per se; 2) the combination of Nox1 with GMC cytosol is insufficient for a significant O(2)(-) generation; 3) the combination with neutrophil cytosol enables Nox1 to act like gp91(phox), i.e., to produce O(2)(-) appreciably in response to myristate stimulation; 4) Nox1 prefers NADPH to NADH under the in vitro assay with neutrophil cytosol plus myristate (K(m)=10.4 microM); 5) substitution of neutrophil cytosol by a set of recombinant cytosolic components (rp67(phox), rp47(phox), Rac2) is, however, ineffective and still requires GMC cytosol. Thus, Nox1 probably requires an additional cytosolic factor(s). In contrast, GMC cytosol enables cytochrome b(558) to generate plenty of O(2)(-), on condition that rp47(phox) is added. This result suggests that GMC cytosol contains a component with p67(phox)-ability, and also Rac, but lacks p47(phox). These data indicate that GMC Nox1 requires at least a p67(phox) counterpart and Rac to acquire NADPH oxidase activity.

Animals↗
PubMed2002

[Alloxan radical-induced generation of reactive oxygen species in the reaction system of alloxan with ascorbate].

The diabetogenic action of alloxan is thought to be initiated by generation of reactive oxygen species (ROS). Ascorbate can be an antioxidant in a predominantly aqueous environment, such as plasma and extracellular fluids. We have investigated the generation of ROS in the interaction of alloxan with ascorbate. Rapid oxygen consumption was observed in the reactin system of alloxan with ascorbate. The oxygen consumption was suppressed by superoxide dismutase and catalase, suggesting that superoxide and hydrogen peroxide could be generated in the reaction system. In addition, the generation of alloxan radical, an electron reductance of alloxan, and ascorbate free radical (AFR), an electron oxidant of ascorbate, was observed using electron spin resonance (ESR). Under anaerobic conditions, the ESR signal intensity of alloxan radical was significantly increased in comparison with that under aerobic conditions, whereas the intensity of AFR was significantly decreased. These results suggest that alloxan radical and AFR were generated in the reaction system of alloxan with ascorbate, and that the alloxan radical but not AFR reacted with molecular oxygen, resulting in the generation of ROS.

Alloxan↗
PubMed2005

Pulmonary effects of indoor- and outdoor-generated particles in children with asthma.

Most particulate matter (PM) health effects studies use outdoor (ambient) PM as a surrogate for personal exposure. However, people spend most of their time indoors exposed to a combination of indoor-generated particles and ambient particles that have infiltrated. Thus, it is important to investigate the differential health effects of indoor- and ambient-generated particles. We combined our recently adapted recursive model and a predictive model for estimating infiltration efficiency to separate personal exposure (E) to PM2.5 (PM with aerodynamic diameter < or = 2.5 microm) into its indoor-generated (Eig) and ambient-generated (Eag) components for 19 children with asthma. We then compared Eig and Eag to changes in exhaled nitric oxide (eNO), a marker of airway inflammation. Based on the recursive model with a sample size of eight children, Eag was marginally associated with increases in eNO [5.6 ppb per 10-microg/m3 increase in PM2.5; 95% confidence interval (CI), -0.6 to 11.9; p = 0.08]. Eig was not associated with eNO (-0.19 ppb change per 10 microg/m3). Our predictive model allowed us to estimate Eag and Eig for all 19 children. For those combined estimates, only Eag was significantly associated with an increase in eNO (Eag: 5.0 ppb per 10-microg/m3 increase in PM2.5; 95% CI, 0.3 to 9.7; p = 0.04; Eig: 3.3 ppb per 10-microg/m3 increase in PM2.5; 95% CI, -1.1 to 7.7; p = 0.15). Effects were seen only in children who were not using corticosteroid therapy. We conclude that the ambient-generated component of PM2.5 exposure is consistently associated with increases in eNO and the indoor-generated component is less strongly associated with eNO.

Adolescent↗
PubMed1997

Involvement of protein kinase C, phospholipase C, and protein tyrosine kinase pathways in oxygen radical generation by asbestos-stimulated alveolar macrophage.

Although asbestos stimulates oxygen radical generation in alveolar macrophages, the exact mechanism is still not clear. The purpose of this study was to compare the ability of three asbestos fibers (amosite, chrysotile, and crocidolite) to generate oxygen radicals in macrophages and examine the mechanism of this action. All asbestos fibers were able to induce chemiluminescence but chrysotile induced maximal chemiluminescence at higher concentrations than amosite and crocidolite. Protein kinase C (PKC) inhibitors (sphingosine and staurosporine) suppressed the ability of asbestos to induce oxygen radical generation. Phospholipase C (PLC) inhibitors (U73122 and neomycin) and protein tyrosine kinase (PTK) inhibitors (erbstatin and genistein) decreased oxygen radical generation of asbestos-stimulated alveolar macrophages. Oxygen radical generation was not suppressed by an adenylate cyclase activator (forskolin), a protein kinase A inhibitor (H-8), and a protein serine-threonine phosphatase inhibitor (okadaic acid). PLC and PTK inhibitors suppressed the increment of phosphoinositide turnover by amosite. These results suggest that asbestos fibers induce the generation of oxygen radicals through PTK, PLC, and PKC pathways in a dose-response pattern.

Animals↗
PubMed2002

Sebaceous epithelial cell differentiation requires cyclic adenosine monophosphate generation.

The cyclic adenosine monophosphate (cAMP) generator choleratoxin is known to promote the growth of sebaceous epithelial cells (sebocytes) in monolayer culture in classical serum-containing media. Now that sebocytes can be grown in serum-free medium, we have examined whether choleratoxin or other cAMP generators are required for differentiation of rat preputial sebocytes in response to specific ligand activators of peroxisome proliferator-activated receptors (PPARs). Unexpectedly, choleratoxin reduced sebocyte proliferation. However, sebocyte differentiation in response to specific PPARalpha and PPARgamma agonists required a cAMP generator such as choleratoxin, and this response was suppressed by a protein kinase A inhibitor. In contrast, the stable prostacyclin analog, carbaprostacyclin (cPGI2), a PPARalpha,delta agonist that also generates cAMP, stimulated differentiation independently of choleratoxin. Furthermore, unlike the selective PPARalpha and PPARgamma agonists, cPGI2 stimulated both sebocyte DNA synthesis and proliferation. These data are compatible with the evidence that prostacyclin has the additional effect of generating cAMP. In addition, we addressed the possibility that choleratoxin may act as a surrogate for beta-adrenergic catecholamines in generating cAMP. In contrast with choleratoxin, both alpha- and beta-adrenergic catecholamines stimulated sebocyte growth and interfered with the choleratoxin effect on differentiation. These data suggest ligand-dependent, complex interactions between cAMP and the other signal transduction pathways involved in sebocyte growth and development.

Animals↗
PubMed2005

Differential effects of hyperosmolality on Na-K-ATPase and vasopressin-dependent cAMP generation in the medullary thick ascending limb and outer medullary collecting duct.

Hyperosmolality in the renal medullary interstitium is generated by the renal countercurrent multiplication system, in which the medullary thick ascending limb (MAL) and the outer medullary collecting duct (OMCD) primarily participate. Since arginine vasopressin (AVP) regulates Na-K-ATPase activity directly via protein kinase A and indirectly via hyperosmolality, we investigated the acute and chronic effects of hyperosmolality on Na-K-ATPase and AVP-dependent cAMP generation in the MAL and OMCD. Microdissected MAL and OMCD from control and dehydrated rats were used for the measurement of Na-K-ATPase activity, mRNA expression of alpha-1, beta-1, and beta-2 subunits of Na-K-ATPase, and AVP-dependent cAMP generation. Na-K-ATPase activity in the MAL from dehydrated rats, as measured in isotonic medium, was higher than that of control rats. Moreover, incubation of samples in hypertonic medium (490 mOsm/kg H2O) further increased Na-K-ATPase activity. Dehydration increased alpha-1, beta-1, and beta-2 mRNA expression in the MAL without changing that in the OMCD. Western blot analysis revealed that in the outer medulla, the expression of beta-1, but not that of alpha-1 or beta-2, was stimulated by dehydration. Incubation of MAL or OMCD in hypertonic medium increased AVP-dependent cAMP generation. Higher levels of AVP-dependent cAMP were generated in the MAL from dehydrated rats than that of controls, although incubation in hypertonic medium did not lead to additional increases in AVP-dependent cAMP accumulation. In contrast, AVP-dependent cAMP generation in the OMCD was stimulated by dehydration, and was further stimulated by incubation in hypertonic medium. These findings demonstrate that Na-K-ATPase is upregulated short- and long-term hyperosmolality in the MAL, but not in OMCD.

Animals↗
PubMed2004

The increase in risk of diabetes mellitus from exposure to second-generation antipsychotic agents.

This is a review of the evidence for a link between exposure to second-generation antipsychotic agents and the development of type 2 diabetes mellitus. Most of this evidence comes from case series and retrospective pharmacoepidemiological studies. Exposure to second-generation antipsychotic agents increases the risk for diabetes mellitus compared to no exposure to antipsychotic drugs. The risk with second-generation antipsychotic agents compared to exposure to first-generation antipsychotics is smaller and not consistent. The differential risk among the second-generation antipsychotic agents has not yet been adequately established. Other risk factors for diabetes mellitus, such as advancing age, non-White ethnicity, family history, obesity, lack of physical activity and the diagnosis of schizophrenia, probably contribute more to the risk than exposure to any single antipsychotic drug. Clinicians are urged to manage risk by regularly monitoring all patients receiving second-generation antipsychotic agents for the emergence of diabetes mellitus.

Antipsychotic Agents↗
PubMed2002

Effect of S-(1,2-dicarboxyethyl) glutathione and S-(1,2-dicarboxyethyl) cysteine on the stimulus-induced superoxide generation and tyrosyl phosphorylation of proteins in human neutrophils.

We investigated the effects of S-(1,2-dicarboxyethyl) glutathione (DCEG) and S-(1,2-dicarboxyethyl) cysteine (DCEC) on the stimulus-induced superoxide generation and tyrosyl phosphorylation of proteins in human neutrophils. When the cells were preincubated with DCEG, the superoxide generation induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) was enhanced in concentration-dependent manner but DCEC showed no effect. The influence of DCEG and DCEC on phorbol 12-myristate 13-acetate-induced superoxide generation showed no effect. On the other hand, the superoxide generation induced by arachidonic acid was markedly suppressed by DCEG and DCEC in concentration-dependent manner. The suppression of DCEG was more effective than that of DCEC. The superoxide generation induced by fMLP in the DCEG-treated cells was suppressed by genistein. DCEG enhanced tyrosyl phosphorylation of 80.0 kDa, 60.0 kDa, and 45.0 kDa proteins in human neutrophils. The tyrosyl phosphorylation of 80.0 kDa, 60.0 kDa, and 45.0 kDa proteins was suppressed by genistein. The enhancement of tyrosyl phosphorylation of these proteins in the DCEG-treated cells was parallel to the enhancement of the fMLP-induced superoxide generation.

Arachidonic Acid↗
PubMed1984

[A generator for producing multicomponent organic solvent vapor in inhalation chambers].

A vapor generator for multicomponent organic solvents was developed and its performance was investigated experimentally. The vapors were generated from the surface of a sintered sphere of glass beads containing the organic solvents. The solvents were automatically supplied from the solvent reservoir to the sphere by suction pressure caused by the evaporation of the solvents and the generated vapors kept at constant high concentration over a long period. The vapor concentration increased with the decreasing flow rate and the increasing gas temperature. The concentration ratio of the generated vapor was found to be equivalent to the mixing ratio of solvents in the reservoir, so this device can generate multicomponent organic solvent vapors at any concentration ratio. The vapor generator is simple to construct and is recognized to be useful for investigation of inhalation toxicities of multicomponent organic solvent vapors.

Atmosphere Exposure Chambers↗
PubMed1994

[Generation of fiber aerosol by ultrasonic nebulizer].

In this study, our point of view is to generate monodisperse fiber aerosols stably from liquid suspension by using an ultrasonic nebulizer. To fulfill this purpose, we set standard operating conditions in advance by measuring relative humidity of the air flowed from the apparatus, and then generated three kinds of fiber aerosols (potassium titanate whisker, amosite, chrysotile) to investigate this method. The results which were obtained are as follows. 1) Nebulizing method is useful for generating fiber aerosols stably. The longest term obtained in stable generation was as much as 6 hours, and the count median length (CML) of the fibers were 1-2 micrometer. 2) The aerosol concentration ranged from 0.2 to 3.4 mg/m3, and the flow rate of carrier air was found most effective to control aerosol concentration and length. 3) To shift the concentration of liquid suspension was not always effective to shift the aerosol concentration, and too much concentrated suspension tended to cause fiber co-aggregation. 4) Primary fiber sample should be fine to generate fiber aerosol stably, because large-sized fibers will disturb the aerosol generation.

Aerosols↗
PubMed2006

Caffeine effect on mortality and oviposition in successive generations of Aedes aegypti.

OBJECTIVE: Previous experiments showed that caffeine blocks the development of Aedes aegypti (Diptera, Culicidae) in the larval stage, consequently inhibiting the production of adults. This study aimed at obtaining data suggestive of caffeine resistance by these mosquitoes. METHODS: Experiments were carried out in successive generations to assess adult production from eggs laid in previous generation and oviposition rate in every generation using 200 and 500 microg/mL caffeine. Tap water was used as control. Experiments were conducted in the city of São José do Rio Preto, Southeastern Brazil between 2002 and 2005. Statistical tests consisted of exploratory data analysis and smoothing algorithms. RESULTS: Increasing reduction in productivity of adults occurred among generations at both caffeine concentrations but the differences were only significant at 200microg/mL caffeine. As for the oviposition rate, there was a decrease in the mean number of eggs per female over generations at both caffeine concentrations. CONCLUSIONS: There was no evidence of caffeine resistance over generations. The study results corroborate caffeine as an alternative as an important Ae. Aegypti control agent to avoid resistance.

Aedes↗
PubMed1989

Generation of hydrogen peroxide in cultured porcine thyroid cells: synergistic regulation by cytoplasmic free calcium and protein kinase C.

This study set out to elucidate the mechanism by which H2O2 generation is regulated in cultured porcine thyroid cells. We monitored continuously the effects of the calcium ionophore A23187 and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) on H2O2 generation, using homovanillic acid and horseradish peroxidase. A23187 and TPA stimulated H2O2 generation. A23187 increased cytoplasmic free calcium and TPA activated protein kinase C. Generation of H2O2 is therefore regulated by cytoplasmic free calcium and protein kinase C. Exposure to A23187 or TPA augmented further the stimulation of H2O2 generation by TPA or A23187 respectively. Thus A23187 and TPA, by increasing cytoplasmic free calcium and activating protein kinase C respectively, synergistically activate H2O2 generation.

Animals↗
PubMed1993

Second generation logarithmic estimates of single-pool variable volume Kt/V: an analysis of error.

The original formula proposed to estimate variable-volume single-pool (VVSP) Kt/V was Kt/V = -In(R - 0.008 * t - f * UF/W), where in the Kt/V range of 0.7 to 1.3, f = 1.0 (* denotes multiplication). This formula tends to overestimate Kt/V as the Kt/V increases above 1.3. Because higher Kt/V values are now commonly delivered, the validity of both the urea generation term (0.008 * f) and correction for UF/W were explored by solving VVSP equations for simulated hemodialysis situations, with Kt/V ranging from 0.6 to 2.6. The analysis led to the development of a second-generation formula, namely: Kt/V = -In(R - 0.008 * t) + (4-3.5 * R) * UF/W. The first and second generation formulas were then used to estimate the modeled VVSP Kt/V in 500 modeling sessions in which the Kt/V ranged widely from 0.7 to 2.1. An analysis of error showed that this second-generation formula eliminated the overestimation of Kt/V in the high ranges found with the first-generation formula. Also, total error (absolute value percent error + 2 SD) was reduced with the second-generation formula. These results led to the proposal of a new formula that can be used for a very wide range of delivered Kt/V.

Computer Simulation↗