Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.3.1 (NADPH oxidase)
 11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incubation of neutrophils with cytokines such as granulocyte macrophage colony-stimulating factor (GM-CSF) delays their loss of function and changes in cellular morphology that are characteristic of apoptosis. Adenosine triphosphate (ATP) and the diadenosine polyphosphates Ap4A and AP3A were almost as effective as GM-CSF in delaying neutrophil apoptosis. The nucleotides could thus preserve cellular morphology, protect against chromatin fragmentation, and preserve functions such as NADPH oxidase activity and expression of CD16. Moreover, addition of ATP, AP3A and AP4A together with GM-CSF resulted in more pronounced protection from apoptosis than was observed during incubation with either the cytokine or the nucleotides alone. Because ATP, Ap3A, and AP4A may be secreted from activated platelets, these observations suggest that platelet-derived products, perhaps acting in combination with endothelial-derived or immune cell-derived cytokines, can regulate neutrophil function during certain types of inflammation.
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PMID:The diadenosine polyphosphates Ap3A and Ap4A and adenosine triphosphate interact with granulocyte-macrophage colony-stimulating factor to delay neutrophil apoptosis: implications for neutrophil: platelet interactions during inflammation. 860 63

Vascular injury after balloon angioplasty results in the rapid activation of platelets leading to the release of growth factors and vasoactive substances. In addition, up-regulation of tissue factor (TF) and an increased production of reactive oxygen species (ROS) have been detected at sites of vascular injury. We investigated whether platelet-derived products (PDP) released from activated human platelets increase ROS production, resulting in the induction of TF expression in vascular smooth muscle cells (SMC). PDP induced a time- and concentration-dependent increase in ROS generation in cultured SMC that was mediated mainly by PDGF-AB and TGF-beta1 and impaired by the flavin inhibitor diphenylene iodonium. Increased ROS formation was associated with enhanced mRNA levels of the small NAD(P)H oxidase subunit p22phox or its smooth muscle isoform. Transient transfection with a p22phox antisense vector decreased PDP-induced ROS generation. PDP up-regulated TF mRNA expression, which was redox sensitive and reduced by transfection of the p22phox antisense vector. In addition, PDP-stimulated reporter gene activity of two TF promoter constructs was decreased by coexpression of the p22phox antisense vector. These results indicate that activated platelets up-regulate TF expression and that this response involves ROS generation and a p22phox-containing NAD(P)H oxidase in SMC.
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PMID:Oxidative stress and expression of p22phox are involved in the up-regulation of tissue factor in vascular smooth muscle cells in response to activated platelets. 1092 86

Platelets, although not phagocytotic, have been suggested to release O. Since O-producing reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidases can be specifically activated by certain agonists and are found in several nonphagocytotic tissues, we investigated whether such an enzyme is the source of platelet-derived O. We further studied which agonists cause platelet O release and whether platelet-derived O influences thrombus formation in vitro. Collagen, but not adenosine 5'-diphosphate (ADP) or thrombin, increased O formation in washed human platelets. This was a reduced nicotinamide adenine dinucleotide (NADH)-dependent process, as shown in platelet lysates. Consistent with a role of a platelet, NAD(P)H oxidase expression of its subunits p47(phox) and p67(phox) and inhibition of platelet O formation by diphenylene-iodoniumchloride (DPI) and by the specific peptide-antagonist gp91ds-tat were observed. Whereas platelet-derived O did not influence initial aggregation, platelet recruitment to a preformed thrombus following collagen stimulation was significantly attenuated by superoxide dismutase (SOD) or DPI. It was also inhibited when ADP released during aggregation was cleaved by the ectonucleotidase apyrase. ADP in supernatants of collagen-activated platelets was decreased in the presence of SOD, resulting in lower ADP concentrations available for recruitment of further platelets. Exogenous O increased ADP- concentrations in supernatants of collagen-stimulated platelets and induced irreversible aggregation when platelets were stimulated with otherwise subthreshold concentrations of ADP. These results strongly suggest that collagen activation induces NAD(P)H oxidase-dependent O release in platelets, which in turn enhances availability of released ADP, resulting in increased platelet recruitment.
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PMID:NAD(P)H oxidase-dependent platelet superoxide anion release increases platelet recruitment. 1213 May 3

Sepsis remains one of the leading causes of death in intensive care units, despite recent acquired knowledge on pathophysiology and treatment. Several mediators of inflammation and cellular damage have been implicated in the complex host-pathogen interaction underlying organ damage and multisystem organ failure , which are hallmarks of sepsis and common causes of death. Among such mediators, reactive oxygen/nitrogen species have been increasingly studied in the context of direct cytotoxicity as well as altered cell signaling. While the generation of reactive oxygen species by inflammatory cells in sepsis is well known, recent studies have shown that vascular cells are able to release reactive oxygen intermediates that may be associated with endothelial dysfunction of sepsis. These compounds can activate transcription factors such as NF-kappaB that sustain inflammatory process or enzymatic systems like poly(ADP-ribose) polymerase-1, which are involved in apoptosis and cytotoxicity of sepsis. Our laboratory recently showed that platelet-derived exosomes from septic patients carry components of a superoxide-producing NADPH oxidase and can, at least in vitro, induce apoptosis of endothelial and vascular smooth muscle cells by a ROS-dependent pathway. Taken together, these data show that reactive oxygen species are involved in cell signaling and organ injury in sepsis. Efforts must be made to identify the precise contribution of these factors in septic process, in order to clarify the mechanisms associated with the disease. This will certainly lead to discovery of therapeutic strategies that can help us to mitigate vascular dysfunction of sepsis.
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PMID:Redox mechanisms of vascular cell dysfunction in sepsis. 1678 90

The generation of reactive oxygen species (ROS) represents a pivotal element of phagocyte defense against microbial invaders. However, oxidative stress also participates in pathophysiological processes of vascular damage leading to cell death of endothelial cells (EC). Currently, ROS-producing cells involved in this process as well as the corresponding extracellular signals required for their activation are ill-defined. In this study, we investigate the impact of the platelet-derived CXC chemokine platelet factor 4 (PF4/CXCL4) on the interaction of human monocytes and EC. We can show for the first time that PF4-activated monocytes become cytotoxic for EC but not epithelial cells. Cytotoxicity was time- and dose-dependent, and earliest effects were seen after 15 h of culture and at a concentration from 0.125 microM PF4 up. By performing transwell experiments and by using specific inhibitory antibodies, we could show that direct cell contact between effector and target cells, mediated by beta(2)integrins as well as their corresponding ligand ICAM-1, is essential for the cytotoxic effect. Investigations of the cellular mechanisms of cytotoxicity revealed that in the presence of EC, PF4-activated monocytes are capable of releasing high amounts of ROS for more than 2 h following stimulation. This causes programmed cell death in EC, as inhibitors of the NADPH oxidase (diphenyleneiodonium and apocynin) effectively blocked PF4-induced monocyte oxidative burst and protected EC from undergoing apoptosis. Taken together, our data suggest a role for platelet-derived PF4 in oxidative stress-mediated vascular disorders, as observed during atherosclerosis or ischemia/reperfusion injury.
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PMID:Platelet factor 4/CXCL4-stimulated human monocytes induce apoptosis in endothelial cells by the release of oxygen radicals. 1820 73

Thymidine phosphorylase (TP) is a rate-limiting enzyme in the thymidine catabolic pathway. TP is identical to platelet-derived endothelial cell growth factor and contributes to tumour angiogenesis. TP induces the generation of reactive oxygen species (ROS) and enhances the expression of oxidative stress-responsive genes, such as interleukin (IL)-8. However, the mechanism underlying ROS induction by TP remains unclear. In the present study, we demonstrated that TP promotes NADPH oxidase-derived ROS signalling in cancer cells. NADPH oxidase inhibition using apocynin or small interfering RNAs (siRNAs) abrogated the induction of IL-8 and ROS in TP-expressing cancer cells. Meanwhile, thymidine catabolism induced by TP increased the levels of NADPH and intermediates of the pentose phosphate pathway (PPP). Both siRNA knockdown of glucose 6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme in PPP, and a G6PD inhibitor, dihydroepiandrosterone, reduced TP-induced ROS production. siRNA downregulation of 2-deoxy-D-ribose 5-phosphate (DR5P) aldolase, which is needed for DR5P to enter glycolysis, also suppressed the induction of NADPH and IL-8 in TP-expressing cells. These results suggested that TP-mediated thymidine catabolism increases the intracellular NADPH level via the PPP, which enhances the production of ROS by NADPH oxidase and activates its downstream signalling.
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PMID:Thymidine catabolism promotes NADPH oxidase-derived reactive oxygen species (ROS) signalling in KB and yumoto cells. 2971 62