Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Brief exposure of cultured rat glomerular mesangial cells (GMC) to H2O2 in nominally bicarbonate-free solution induced a rapid dose dependent, dantrolene-inhibitable increase in intracellular free Ca2+ from 65 +/- 6 to 203 +/- 14 nmol/L and a prolonged release of [14C]-arachidonic acid [14C]-AA which preceded the onset of cell membrane damage assessed by trypan-blue uptake. 2. Ca2+ responses were potentiated in HCO3-/CO2 containing buffers and reached values of 1145 +/- 100 nmol/L at 1 mmol/L H2O2. In HCO3-/CO2 solutions, but not HEPES buffer, H2O2-induced Ca2+ increases were markedly attenuated by verapamil (100 mumol/L) or removal of extracellular calcium. 3. Enhanced release of [14C]-AA was partially attenuated by inhibitors of key intracellular signalling mechanisms including the phospholipase-A2 (PLA2) inhibitor mepacrine (100 mumol/L), the NADPH oxidase inhibitor diphenyliodonium (10 mumol/L), the mitochondrial calcium-cycling inhibitor ruthenium red (10 mumol/L) and the iron chelator dipyridyl (100 mumol/L). Release was unaffected by protein kinase C inhibition with H7 (100 mumol/L), inositol triphosphate antagonism with neomycin (1 mmol/L) or overnight treatment with the G-protein antagonist pertussis toxin (5 micrograms/mL). 4. Several structurally diverse lipoxygenase inhibitors, including esculetin, baicalein and phenidone, over the dose range 1-100 mumol/L, also prevented [14C]-AA release and markedly protected against cell membrane damage. No drug directly scavenged H2O2 assessed by UV absorption. 5. These results indicate that H2O2 activates in GMC a complex series of interrelated pathological mechanisms which in turn contribute to a prolongation of oxidative damage beyond the time of the initial exposure. These include an increase in intracellular calcium which, depending upon conditions, appears to be mediated by release from intracellular stores as well as Ca2+ entry from the extracellular space. In turn there is a sustained release of arachidonic acid, which may partly depend on prolonged activation of PLA2 but not phospholipase C. 6. Release of [14C]-AA could be attenuated by inhibitors of NADPH oxidase, mitochondrial calcium-cycling, iron chelators and a structurally diverse range of lipoxygenase inhibitors in association with protection from H2O2-mediated cell membrane damage.
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PMID:Role of intracellular signalling pathways in hydrogen peroxide-induced injury to rat glomerular mesangial cells. 884 14

Exogenous sphingosine 1-phosphate (S1P) stimulated hydrogen peroxide (H2O2) generation in association with an increase in intracellular Ca2+ concentration in FRTL-5 thyroid cells. S1P also induced inositol phosphate production, reflecting activation of phospholipase C (PLC) in the cells. These three S1P-induced events were inhibited partially by pertussis toxin (PTX) and markedly by U73122, a PLC inhibitor, and were conversely potentiated by N6-(L-2-phenylisopropyl)adenosine, an A1-adenosine receptor agonist. In FRTL-5 cell membranes, S1P also activated PLC in the presence of guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S), but not in its absence. Guanosine 5'-O-(2-thiodiphosphate) inhibited the S1P-induced GTP gamma S-dependent activation of the enzyme. To characterize the signaling pathways, especially receptors and G proteins involved in the S1P-induced responses, cross-desensitization experiments were performed. Under the conditions where homologous desensitization occurred in S1P-, lysophosphatidic acid (LPA)-, and bradykinin-induced induction of Ca2+ mobilization, no detectable cross-desensitization of S1P and bradykinin was observed. This suggests that the primary action of S1P in its activation of the PLC-Ca2+ system was not the activation of G proteins common to S1P and bradykinin, but the activation of a putative S1P receptor. On the other hand, there was a significant cross-desensitization of S1P and LPA; however, a still significant response to S1P (50-80% of the response in the nontreated control cells) was observed depending on the lipid dose employed after a prior LPA challenge. S1P also inhibited cAMP accumulation in a PTX-sensitive manner. We conclude that S1P stimulates H2O2 generation through a PLC-Ca2+ system and also inhibits adenylyl cyclase in FRTL-5 thyroid cells. The S1P-induced responses may be mediated partly through a putative lipid receptor that is coupled to both PTX-sensitive and insensitive G proteins.
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PMID:Sphingosine 1-phosphate stimulates hydrogen peroxide generation through activation of phospholipase C-Ca2+ system in FRTL-5 thyroid cells: possible involvement of guanosine triphosphate-binding proteins in the lipid signaling. 897 7

Human fat cells possess a multireceptor-linked H2O2-generating system that is activated by insulin. Previous studies revealed that manganese was the sole cofactor required for a hormonal regulation of NADPH-dependent H2O2 generation in vitro. In this report it is shown that the synergistic activation of NADPH-dependent H2O2 generation by Mn2+ and insulin was blocked by GDPbetaS (guanosine 5'-O-(2-thiodiphosphate)), pertussis toxin and COOH-terminal anti-Galphai1-2 or the corresponding peptide. Consistently, manganese could be replaced by micromolar concentrations of GTPgammaS (guanosine 5'-O-(3-thiotriphosphate)), which increased NADPH-dependent H2O2 generation by 20-40%. Insulin shifted the dose response curve for GTPgammaS to the left (>10-fold) and increased the maximal response. In the presence of 10 microM GTPgammaS, the hormone was active at picomolar concentrations, indicating that insulin acted via its cognate receptor. The insulin receptor and Gi were co-adsorbed on anti-Galphai and anti-insulin receptor beta-subunit (anti-IRbeta) affinity columns. Partially purified insulin receptor preparations contained Galphas, Galphai2, and Gbetagamma (but no Galphai1 or Galphai3). The functional nature of the insulin receptor-Gi2 complex was made evident by insulin's ability to modulate labeling of Gi by bacterial toxins. Insulin action was mimicked by activated Galphai, but not by Galphao or Gbetagamma, indicating that insulin's signal was transduced via Galphai2. Thus, NADPH oxidase is the first example of an effector system that is coupled to the insulin receptor via a heterotrimeric G protein.
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PMID:Insulin-induced activation of NADPH-dependent H2O2 generation in human adipocyte plasma membranes is mediated by Galphai2. 909 59

Human neutrophils (PMN) activated by N-formylmethionyl-leucyl-phenylalanine (fMLP) simultaneously release nitric oxide (.NO), superoxide anion (O2.-) and its dismutation product, hydrogen peroxide (H2O2). To assess whether .NO production shares common steps with the activation of the NADPH oxidase, PMN were treated with inhibitors and antagonists of intracellular signaling pathways and subsequently stimulated either with fMLP or with a phorbol ester (PMA). The G-protein inhibitor, pertussis toxin (1-10 micrograms/ml) decreased H2O2 yield without significantly changing .NO production in fMLP-stimulated neutrophils; no effects were observed in PMA-activated cells. The inhibition of tyrosine kinases by genistein (1-25 micrograms/ml) completely abolished H2O2 release by fMLP-activated neutrophils; conversely, .NO production increased about 1.5- and 3-fold with fMLP and PMA, respectively. Accordingly, orthovanadate, an inhibitor of phosphotyrosine phosphatase, markedly decreased .NO production and increased O2.- release. On the other hand, inhibition of protein kinase C with staurosporine and the use of burst antagonists like adenosine, cholera toxin or dibutyryl-cAMP diminished both H2O2 and .NO production. The results suggest that the activation of the tyrosine kinase pathway in stimulated human neutrophils controls positively O2.- and H2O2 generation and simultaneously maintains .NO production in low levels. In contrast, activation of protein kinase C is a positive modulator for O2.- and .NO production.
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PMID:Effects of respiratory burst inhibitors on nitric oxide production by human neutrophils. 916 37

Cultured human and rat endothelial cells were used to study cellular toxicity and Ca2+ signalling upon exposure to reactive oxygen species. Superoxide and hydrogen peroxide (O2.-/H2O2) were produced by the hypoxanthine/xanthine oxidase system (HX/XO) and caused intracellular Ca2+ concentration ([Ca2+]i) to rise steadily when activities above 2 mU/ml were used. These Ca2+ increases were also measured when the glucose/glucose oxidase (G/GO) system above 5 mU/ml was used to produce hydrogen peroxide (H2O2). Gross morphological changes appeared to parallel elevated [Ca2+]i levels preceding cell death. However, when HX/XO or G/GO were used at non toxic doses rapid and transient changes in [Ca2+]i were measured. These treatments did not alter subsequent receptor mediated Ca2+ signalling induced by ATP (10 microM) or histamine (100 microM). Superoxide dismutase (50 U/ml), which dismutates O2.- into H2O2 also had no influence, whereas catalase (50 U/ml), which removes H2O2, completely diminished transient [Ca2+]i responses. H2O2 added directly was able to induce similar Ca2+ transients when concentrations of at least 500 microM were used. Buffering trace amounts of iron (o-phenanthroline; 200 microM) in order to inhibit .OH radical formation was not effective to alter Ca2+ changes. Experiments performed in Ca(2+)-free buffer showed a similar rise in [Ca2+]i and readdition of Ca2+ to the extracellular medium indicated the activation of store operated Ca2+ entry. Blocking Ca(2+)-ATPases of the endoplasmatic reticulum with thapsigargin (1 microM) inhibited ROS induced transient increases and cells preincubated with pertussis toxin (200 nM) showed unchanged Ca2+ transients after exposure to both enzyme systems. Phospholipase C inhibitor U73122 (2 microM) effectively reduced hydrogen peroxide induced emptying of intracellular stores. Taken together, we demonstrate that enzymatically produced non-toxic H2O2 rather than O2.- or .OH causes calcium signalling from thapsigargin sensitive stores, and activates store operated Ca2+ entry at least partially by activating phospholipase C. These changes clearly differ from pathological 'oxidative stress' associated with a progressive increase in [Ca2+]i.
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PMID:Transient Ca2+ changes in endothelial cells induced by low doses of reactive oxygen species: role of hydrogen peroxide. 920 90

To assess the effects of oxyradicals on cardiac beta-adrenoceptors, G-proteins and adenylyl cyclase, rat heart membranes were incubated with xanthine (X) plus xanthine oxidase (XO) for different intervals. The basal as well as forskolin-, NaF-, 5'-guanylylimidodiphosphate and isoproterenol-stimulated adenylyl cyclase activities showed an increase at 10 min and a decrease at 30 min of incubation with X plus XO. Treatment of membranes with H2O2 also produced biphasic changes in adenylyl cyclase activities. The density of beta1-adrenoceptors was decreased when cardiac membranes were treated with X plus XO for 10 and 30 min whereas the affinity of beta1-adrenoceptors was increased after 10 min and reduced after 30 min of incubation. The beta2-adrenoceptors were not modified at 10 min whereas incubation of cardiac membranes with X plus XO for 30 min increased the affinity and decreased the density. Cholera toxin-stimulated adenylyl cyclase activity, cholera toxin-catalyzed ADP-ribosylation and stimulatory guanine nucleotide binding protein immunoreactivity in cardiac membranes were increased at 10 min and decreased at 30 min of incubation with X plus XO. However, the pertussis toxin-stimulated adenylyl cyclase activity, pertussis toxin-catalyzed ADP ribosylation and inhibitory guanine nucleotide binding protein immunoreactivity were not affected on treatment of membranes with X plus XO. Addition of superoxide dismutase plus catalase in the incubation medium prevented the X plus XO-induced alterations in adenylyl cyclase activities, stimulatory guanine nucleotide binding protein-related ADP-ribosylation and changes in the characteristics of beta-adrenoceptors except the increased affinity of beta1-adrenoceptors at 10 min of incubation. These data suggest that alterations in the beta1-adrenoceptor-linked stimulatory guanine nucleotide binding protein-adenylyl cyclase pathway due to X plus XO are biphasic in nature and these changes may likely be due to the formation of H2O2.
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PMID:Biphasic alterations in cardiac beta-adrenoceptor signal transduction mechanism due to oxyradicals. 931 80

From the role of oxidative stress in cardiac dysfunction, we investigated the effect of H2O2, an activated species of oxygen, on beta-adrenoceptors, G proteins, and adenylyl cyclase activities. Rat heart membranes were incubated with different concentrations of H2O2 before the biochemical parameters were measured. Both the affinity and density of beta 1-adrenoceptors were decreased, whereas the density of the beta 2-adrenoceptors was decreased and the affinity was increased by 1 mM H2O2. Time- and concentration-dependent biphasic changes in adenylyl cyclase activities in the absence or presence of isoproterenol were observed when membranes were incubated with H2O2; however, activation of the enzyme by isoproterenol was increased or unaltered. The adenylyl cyclase activities in the absence or presence of forskolin, NaF, and Gpp(NH)p were depressed by H2O2. Catalase alone or in combination with mannitol was able to significantly decrease the magnitude of alterations due to H2O2. The cholera toxin-stimulated adenylyl cyclase activity and ADP ribose labeling of Gs proteins were decreased by treatment with 1 mM H2O2, whereas Gi protein activities, as reflected by pertussis toxin-stimulation of adenylyl cyclase and ADP ribosylation, were unaltered. The Gs and Gi protein immunoreactivities, estimated by labeling with respective antibodies, indicate a decrease in binding to the 45-kDa band of Gs protein, whereas no change in the binding of antibodies to the 52-kDa band of Gs protein or the 40-kDa subunit of Gi protein was evident when the membranes were treated with 1 mM H2O2. These results suggest that H2O2 in high concentrations may attenuate the beta-adrenoceptor-linked signal transduction in the heart by changing the functions of Gs proteins and the catalytic subunit of the adenylyl cyclase enzyme.
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PMID:Modification of cardiac beta-adrenoceptor mechanisms by H2O2. 948 43

Experiments were designed to investigate whether leukotriene (LTB4) receptors can couple directly to phospholipase A2 (PLA2) in guinea pig eosinophils and the role of endogenous arachidonic acid (AA) in LTB4-induced activation of the NADPH oxidase. LTB4 (EC50 approximately 16 nM) and AA (EC50 approximately 6 microM) generated hydrogen peroxide (H2O2) in a concentration-dependent manner and at an equivalent maximum rate (5-6 nmol/min/10(6) cells). LTB4 stimulated PLA2 over a similar concentration range that activated the NADPH oxidase, although kinetic studies revealed that the release of [3H]AA (t1/2 approximately 2 s) preceded H2O2 generation (t1/2 > 30 s). Pretreatment of eosinophils with pertussis toxin abolished the increase in inositol(1,4,5)trisphosphate mass, [Ca2+]c, [3H]AA release, and H2O2 generation evoked by LTB4. Qualitatively identical results were obtained in eosinophils in which phospholipase C (PLC) was desensitized by 4beta-phorbol 12,13-dibutyrate with the exception that [3H]AA release was largely unaffected. Additional studies performed with the protein kinase C inhibitor, Ro 31-8220, and under conditions in which Ca2+ mobilization was abolished, provided further evidence that LTB4 released [3H]AA independently of signal molecules derived from the hydrolysis of phosphatidylinositol(4,5)bisphosphate by PLC. Pretreatment of eosinophils with the PLA2 inhibitor, mepacrine, abolished LTB4-induced [3H]AA release at a concentration that inhibited H2O2 by only 36%. Collectively, the results of this study indicate that agonism of LTB4 receptors on guinea pig eosinophils mobilizes AA by a mechanism that does not involve the activation of PLC. In addition, although LTB4 effectively stimulated PLA2, a central role for AA in the activation of the NADPH oxidase was excluded.
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PMID:Leukotriene B4 activates the NADPH oxidase in eosinophils by a pertussis toxin-sensitive mechanism that is largely independent of arachidonic acid mobilization. 957 59

Although class A type I/II scavenger receptor (SR-A) is involved in numerous macrophage functions, its signaling ability remains uncertain. We used monoclonal antibodies (mAb) to specifically stimulate receptors on mouse alveolar (AMs) and peritoneal macrophages (PMs). Immobilized anti-SR-A (2F8) and anti-FcgammaR II/III (2.4G2) mAb stimulated hydrogen peroxide (H2O2) production in normal C3H/HeJ AMs (by 55% and 98%, respectively) and resident PMs (66% and 128%). The 2F8 mAb-stimulated H2O2 production resulted from specific stimulation of SR-A, since this response was absent in AMs from SR-A-deficient or C57BL/6 mice--the latter strain expressing an allelic form of SR-A, unrecognizable by 2F8 mAb. H2O2 production stimulated by anti-SR-A but not by anti-FcgammaRII/III mAb was preserved in FcgammaRI/III-deficient mice, ruling out involvement of FcgammaRs in the 2F8 mAb effect. In comparison with the FcgammaR-stimulated respiratory burst, the response to anti-SR-A mAb was delayed and, unlike the former, inhibited by pertussis toxin. Ligation of SR-A also inhibited lipopolysaccharide plus interferon-gamma-stimulated interleukin-12 (IL-12) release, by 25% in AMs and by 68% in thioglycollate-elicited PMs, consistent with different levels of SR-A expression. Neither nitrite nor IL-6 accumulation was affected by anti-SR-A mAb. SR-A-stimulated H2O2 does not seem to mediate the inhibition of IL-12 release, since the inhibition was neither reversed by scavenging of H2O2 nor mimicked by exogenous H2O2. Our results indicate that SR-A not only mediates endocytosis but can also generate signals such as H2O2, which may affect microbicidal or proinflammatory functions.
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PMID:Scavenger receptor A mediates H2O2 production and suppression of IL-12 release in murine macrophages. 1531 30

CB1 cannabinoid receptors (CB1Rs) are involved in protecting the brain from ischemia and related disorders. However, the underlying protective mechanisms are incompletely understood. We investigated the effect of CB1R activation on oxidative injury, which has been implicated in neuronal death after cerebral ischemia and neurodegenerative disorders, in mouse cortical neuron cultures. The CB1R agonist Win 55212-2 [R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate] reduced neuronal death, measured by lactate dehydrogenase release, in cultures treated with 50 microM FeCl2, and its protective effect was attenuated by the CB1R antagonist SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-cichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride]. The endocannabinoid anandamide reproduced the effect of Win 55212-2, as did the antioxidant 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). Neuronal injury was more severe after in vitro or in vivo administration of FeCl2 to CB1R-knockout compared with wild-type mice. Win 55212-2 reduced the formation of reactive oxidative species in cortical neuron cultures treated with FeCl2, consistent with an antioxidant action. Pertussis toxin reduced CB1R-mediated protection, which points to a protective mechanism that involves signaling through G(i/o) proteins. Since CB1R-activated G protein signaling inhibits protein kinase A but activates phosphatidylinositol 3-kinase (PI3K), we tested the involvement of these pathways in CB1R-mediated neuroprotection. Dibutyryl-cyclic adenosine monophosphate (dbcAMP) blocked protection by Win 55212-2, whereas the PI3K inhibitor wortmannin did not, and the effect of dbcAMP was inhibited by the protein kinase A inhibitor H89 [N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide] (> or =10 nM). CB1R-induced, SR141716A-, pertussis toxin-, and dbcAMP-sensitive protection was also observed for two other oxidative insults, exposure to H2O2 or buthionine sulfoximine. Therefore, receptor-stimulated inhibition of protein kinase A seems to be required for the neuroprotective effect of CB1R activation against oxidative neuronal injury.
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PMID:Involvement of protein kinase A in cannabinoid receptor-mediated protection from oxidative neuronal injury. 1562 18


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