Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.3.1 (NADPH oxidase)
11,281 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydrogen peroxide (H2O2) is known to both induce and inhibit apoptosis, however the mechanisms are unclear. We found that H2O2 inhibited the activity of recombinant caspase-3 and caspase-8, half-inhibition occurring at about 17 microM H2O2. This inhibition was both prevented and reversed by dithiothreitol while glutathione had little protective effect. 100-200 microM H2O2 added to macrophages after induction of caspase activation by nitric oxide or serum withdrawal substantially inhibited caspase activity. Activation of H2O2-producing NADPH oxidase in macrophages also caused catalase-sensitive inactivation of cellular caspases. The data suggest that the activity of caspases in cells can be directly but reversibly inhibited by H2O2.
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PMID:Caspases are reversibly inactivated by hydrogen peroxide. 1144 67

Phagocytosis of complement-opsonized targets is a primary function of neutrophils at sites of inflammation, and the clearance of neutrophils that have phagocytosed microbes is important for the resolution of inflammation. Our previous work suggests that phagocytosis leads to rapid neutrophil apoptosis that is inhibited by antibody to the beta2 integrin, Mac-1, and requires NADPH oxidase-derived reactive oxygen species (ROS) generated during phagocytosis. Here we report that phagocytosis-induced cell death (PICD) does not occur in Mac-1-deficient murine neutrophils, suggesting that PICD proceeds through a bona fide Mac-1-dependent pathway. A sustained, intracellular oxidative burst is associated with PICD. Furthermore, PICD does not require traditional death receptors, Fas, or tumor necrosis factor (TNF) receptor. TNF but not Fas synergizes with phagocytosis to enhance significantly PICD by increasing the oxidative burst, and this is Mac-1-dependent. Phagocytosis-induced ROS promote cleavage/activation of caspases 8 and 3, key players in most extrinsic ("death receptor") mediated pathways of apoptosis, and caspases 8 and 3 but not caspase 9/mitochondria, are required for PICD. This suggests that ROS target the extrinsic versus the intrinsic ("stress stimulus") apoptotic pathway. Phagocytosis also triggers a competing MAPK/ERK-dependent survival pathway that provides resistance to PICD likely by down-regulating caspase 8 activation. The anti-apoptotic factor granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly enhances ROS generation associated with phagocytosis. Despite this, it completely suppresses PICD by sustaining ERK activation and inhibiting caspase 8 activation in phagocytosing neutrophils. Together, these studies suggest that Mac-1-mediated phagocytosis promotes apoptosis through a caspase 8/3-dependent pathway that is modulated by NADPH oxidase-generated ROS and MAPK/ERK. Moreover, TNF and GM-CSF, likely encountered by phagocytosing neutrophils at inflammatory sites, exploit pro-(ROS) and anti-apoptotic (ERK) signals triggered by phagocytosis to promote or suppress PICD, respectively, and thus modulate the fate of phagocytosing neutrophils.
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PMID:Elucidation of molecular events leading to neutrophil apoptosis following phagocytosis: cross-talk between caspase 8, reactive oxygen species, and MAPK/ERK activation. 1273 63

CD95 ligand (CD95L) triggers a rapid formation of reactive oxygen species (ROS) as an upstream event of CD95 activation and apoptosis induction in rat hepatocytes. This ROS response was sensitive to inhibition by diphenyleneiodonium, apocynin, and neopterin, suggestive of an involvement of NADPH oxidases. In line with this, hepatocytes expressed mRNAs not only of the phagocyte gp91phox (Nox 2), but also of the homologs Nox 1 and 4 and Duox 1 and 2, as well as the regulatory subunit p47phox. gp91phox (Nox 2) and p47phox were also identified at the protein level in rat hepatocytes. CD95L induced within 1 min ceramide formation and serine phosphorylation of p47phox, which was sensitive to inhibitors of sphingomyelinase and protein kinase Czeta (PKCzeta). These inhibitors and p47phox protein knockdown inhibited the early CD95L-induced ROS response, suggesting that ceramide and PKCzeta are upstream events of the CD95L-induced Nox/Duox activation. CD95L also induced rapid activation of the Src family kinase Yes, being followed by activation of c-Src, Fyn, and c-Jun-N-terminal kinases (JNK). Only Yes and JNK activation were sensitive to N-acetylcysteine, inhibitors of NADPH oxidase, PKCzeta, or sphingomyelinase, indicating that the CD95L-induced ROS response is upstream of Yes and JNK but not of Fyn and c-Src activation. Activated Yes rapidly associated with the epidermal growth factor receptor (EGFR), which became phosphorylated at Tyr845 and Tyr1173 but not at Tyr1045. Activated EGFR then triggered an AG1478-sensitive CD95-tyrosine phosphorylation, which was a signal for membrane targeting of the EGFR/CD95 complex, subsequent recruitment of Fas-associated death domain and caspase 8, and apoptosis induction. All of these events were significantly blunted by inhibitors of sphingomyelinase, PKCzeta, NADPH oxidases, Yes, or EGFR-tyrosine kinase activity and after protein knockdown of either p47phox, Yes, or EGFR. The data suggest that CD95L-induced apoptosis involves a sphingomyelinase- and PKCzeta-dependent activation of NADPH oxidase isoforms, which is required for Yes/EGFR/CD95 interactions as upstream events of CD95 activation.
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PMID:Involvement of NADPH oxidase isoforms and Src family kinases in CD95-dependent hepatocyte apoptosis. 1591 50

Solar ultraviolet A (UVA) radiation induces many responses in skin including oxidative stress, DNA damage, inflammation, and skin cancer. Smith-Lemli-Opitz syndrome (SLO-S) patients show dramatically enhanced immediate (5 min) and extended (24-48 h) skin inflammation in response to low UVA doses compared to normal skin. Mutations in Delta7-dehydrocholesterol reductase, which converts 7-dehydrocholesterol to cholesterol, produces high levels of 7-dehydrocholesterol in SLO-S patient's serum. Since 7-dehydrocholesterol is more rapidly oxidized than cholesterol, we hypothesized that 7-dehydrocholesterol enhances UVA-induced oxidative stress leading to keratinocyte death and inflammation. When keratinocytes containing high 7-dehydrocholesterol and low cholesterol were exposed to UVA (10 J/cm2), eightfold greater reactive oxygen species (ROS) were produced than in normal keratinocytes after 15 min. UVA induced 7-dehydrocholesterol concentration-dependent cell death at 24 h. These responses were inhibited by antioxidants, reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor (diphenyleneiodonium) and a mitochondria-specific radical quencher. Cell death was characterized by activation of caspases-3, -8, and -9 and by phosphatidylserine translocation. Studies using antioxidants and specific caspase inhibitors indicated that activation of caspase-8, but not caspase-9, mediates ROS-dependent caspase-3 activation and suggested that ROS from NADPH oxidase activate caspase-8. These results support a ROS-mediated apoptotic mechanism for the enhanced UVA-induced inflammation in SLO-S patients.
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PMID:Ultraviolet A induces apoptosis via reactive oxygen species in a model for Smith-Lemli-Opitz syndrome. 1645 95

In the current study, we examined the effects of the nonpsychoactive cannabinoid, cannabidiol, on the induction of apoptosis in leukemia cells. Exposure of leukemia cells to cannabidiol led to cannabinoid receptor 2 (CB2)-mediated reduction in cell viability and induction in apoptosis. Furthermore, cannabidiol treatment led to a significant decrease in tumor burden and an increase in apoptotic tumors in vivo. From a mechanistic standpoint, cannabidiol exposure resulted in activation of caspase-8, caspase-9, and caspase-3, cleavage of poly(ADP-ribose) polymerase, and a decrease in full-length Bid, suggesting possible cross-talk between the intrinsic and extrinsic apoptotic pathways. The role of the mitochondria was further suggested as exposure to cannabidiol led to loss of mitochondrial membrane potential and release of cytochrome c. It is noteworthy that cannabidiol exposure led to an increase in reactive oxygen species (ROS) production as well as an increase in the expression of the NAD(P)H oxidases Nox4 and p22(phox). Furthermore, cannabidiol-induced apoptosis and reactive oxygen species (ROS) levels could be blocked by treatment with the ROS scavengers or the NAD(P)H oxidase inhibitors. Finally, cannabidiol exposure led to a decrease in the levels of p-p38 mitogen-activated protein kinase, which could be blocked by treatment with a CB2-selective antagonist or ROS scavenger. Together, the results from this study reveal that cannabidiol, acting through CB2 and regulation of Nox4 and p22(phox) expression, may be a novel and highly selective treatment for leukemia.
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PMID:Cannabidiol-induced apoptosis in human leukemia cells: A novel role of cannabidiol in the regulation of p22phox and Nox4 expression. 1675 84

Hyperoxia causes cell injury and death associated with reactive oxygen species formation and inflammatory responses. Recent studies show that hyperoxia-induced cell death involves apoptosis, necrosis, or mixed phenotypes depending on cell type, although the underlying mechanisms remain unclear. Using murine lung endothelial cells, we found that hyperoxia caused cell death by apoptosis involving both extrinsic (Fas-dependent) and intrinsic (mitochondria-dependent) pathways. Hyperoxia-dependent activation of the extrinsic apoptosis pathway and formation of the death-inducing signaling complex required NADPH oxidase-dependent reactive oxygen species production, because this process was attenuated by chemical inhibition, as well as by genetic deletion of the p47(phox) subunit, of the oxidase. Overexpression of heme oxygenase-1 prevented hyperoxia-induced cell death and cytochrome c release. Likewise, carbon monoxide, at low concentrations, markedly inhibited hyperoxia-induced endothelial cell death by inhibiting cytochrome c release and caspase-9/3 activation. Carbon monoxide, by attenuating hyperoxia-induced reactive oxygen species production, inhibited extrinsic apoptosis signaling initiated by death-inducing signal complex trafficking from the Golgi apparatus to the plasma membrane and downstream activation of caspase-8. We also found that carbon monoxide inhibited the hyperoxia-induced activation of Bcl-2-related proteins involved in both intrinsic and extrinsic apoptotic signaling. Carbon monoxide inhibited the activation of Bid and the expression and mitochondrial translocation of Bax, whereas promoted Bcl-X(L)/Bax interaction and increased Bad phosphorylation. We also show that carbon monoxide promoted an interaction of heme oxygenase-1 with Bax. These results define novel mechanisms underlying the antiapoptotic effects of carbon monoxide during hyperoxic stress.
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PMID:Carbon monoxide protects against hyperoxia-induced endothelial cell apoptosis by inhibiting reactive oxygen species formation. 1713 72

Cell shrinkage, nuclear condensation, DNA fragmentation, and apoptotic body formation are hallmarks of programmed apoptotic cell death. Herein, apoptotic volume decrease (AVD) is an early and ubiquitous event. Conversely, in hepatocytes, hyperosmotic cell shrinkage leads to an activation of the CD95 death receptor system, which involves CD95 tyrosine phosphorylation, CD95 oligomerization, and subsequent trafficking of the CD95 to the plasma membrane, and sensitizes hepatocytes toward CD95 ligand (CD95L)-induced apoptosis. Early signaling events leading to CD95 activation by hyperosmolarity have been identified. In hepatocytes, hyperosmotic exposure induces an almost instantaneous acidification of an acidic sphingomyelinase (ASM) containing endosomal compartment, which is followed by an increase in the intracellular ceramide concentration. Inhibition of anion channels or the vacuolar-type H(+)-ATPase abolishes not only endosomal acidification and subsequent ceramide generation, but also the otherwise observed hyperosmotically induced generation of reactive oxygen species (ROS) by NADPH oxidase isoforms. Hyperosmolarity-induced ROS formation then leads to a Src-family kinase Yes-mediated activation of the epidermal growth factor receptor (EGFR) and to an activation of the c-Jun-N-terminal kinase (JNK). JNK then provides a signal for CD95/EGFR association and subsequent CD95 tyrosine phosphorylation, which is mediated by the EGFR tyrosine kinase activity. CD95 tyrosine phosphorylation then allows for CD95 receptor oligomerization, translocation of the CD95/EGFR protein complex to the plasma membrane, and formation of the death inducing signaling complex (DISC). Mild hyperosmotic exposure, that is, 405 mosmol/liter, does not lead to a reduction of cell viability, even if DISC formation and subsequent caspase 8 and 3 activation occur, but sensitizes hepatocytes to CD95L-induced apoptosis. However, activation of the CD95 system by a more severe hyperosmotic challenge (>505 mosmol/liter) is followed by execution of the apoptotic cell death. Other covalent modifications of CD95, such as CD95 tyrosine nitration or CD95 serine/threonine phosphorylation, were shown to inhibit the CD95 activation process.
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PMID:Hyperosmotic activation of the CD95 system. 1787 16

Although in rat hepatocytes CD95 is predominantly located inside the cell with almost undetectable immunostaining at the plasma membrane, the addition of CD95-ligand (CD95L) induces hepatocyte apoptosis, which is preceded by a targeting and activation of intracellularly localized CD95 to the plasma membrane including formation of the death-inducing signaling complex. This process involves an NADPH oxidase-dependent generation of reactive oxygen species (ROS) through a ceramide- and protein kinase Czeta-dependent pathway, which leads to an activating phosphorylation of p47(phox). The mechanisms underlying CD95L-induced ceramide formation were addressed in the present study. It was found that CD95L lowered within seconds the apparent vesicular pH from 6.0 to 5.7 in a fluorescein isothiocyanate-dextran-accessible endosomal compartment, which was previously shown to contain acidic sphingomyelinase, and decreased N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide fluorescence, suggestive for an increase of cytosolic [Cl(-)]. Bafilomycin or 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid disodium salt largely abolished the CD95L-induced endosomal acidification, ceramide formation, and downstream events, such as p47(phox) phosphorylation, ROS formation, CD95 activation, and apoptosis. These responses were also abolished after knock-down of acidic sphingomyelinase in rat hepatocytes. Interestingly, caspase 8 inhibitors abolished these CD95L-induced signaling events, including the increase in cytosolic [Cl(-)], endosomal acidification, ceramide formation, and ROS generation as well as CD95 targeting to the plasma membrane and CD95 activation. The data suggest that CD95L initiates a rapid caspase 8-dependent endosomal acidification, which triggers ceramide-dependent ROS formation as an upstream event of trafficking of intracellularly stored CD95 to the plasma membrane. It is concluded that a rapid caspase 8 activation in response to CD95L signals to intracellularly stored CD95, which becomes activated and targeted to the plasma membrane. This autoamplification of CD95-activation is required for apoptosis induction.
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PMID:Amplification of CD95 activation by caspase 8-induced endosomal acidification in rat hepatocytes. 1804 65

A growing body of evidence suggests oxidative stress involvement in neurodegenerative diseases; however, it remains to be determined whether oxidative stress is a cause, result, or epiphenomenon of the pathological processes. This review concerns the current issue, focusing on Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). Several studies have indicated that oxidative stress initially occurs in the disease-specific, site-restricted sources such as amyloid-beta in the cerebral cortex of AD brain, alpha-synuclein in the brain stem of PD brain, and glutamate receptor-coupled Ca2+ channel in the motor system of ALS spinal cord. Subsequent events in the neurons common to these diseases are glutamate-induced neurotoxicity and increased cytosolic Ca2+ levels, resulting in activation of Ca2+ -dependent enzymes including NADPH oxidase, cytosolic phospholipase A2, xanthine oxidase, and neuronal nitric oxide synthase (NOS). These enzymes produce reactive oxygen and nitrogen species (ROS/RNS), which oxidatively modify nucleic acid, lipid, sugar, and protein, leading to nuclear damage, mitochondrial damage, proteasome inhibition, and endoplasmic reticulum (ER) stress. Mitochondrial damage results in both ROS leakage from the electron transport system and Ca2+ release. Nuclear damage induces p53 activation, and proteasome inhibition reduces p53 degradation. The resultant increased p53 levels in the nucleus induce Bax activation and Bcl-2 inhibition, followed by a release of cytochrome c into the cytosol that truncates procaspase-9. ER stress triggers activation of caspase-12 as well as caspase-9 via the tumor necrosis factor (TNF) receptor-associated factor-2 / apoptosis-signaling kinase-1 / c-Jun N-terminal kinase pathway. Oxidative stress also stimulates astrocytes and microglia to yield and secrete cytokines such as TNFa and FasL that cause not only neuronal caspase-8 activation but also glial inflammatory response through induction of nuclear factor-kappaB-mediated, proinflammatory gene products including cytokines, chemokines, growth factors, cell adhesion molecules, and ROS/RNS-producing enzymes. The activated caspases truncate procaspase-3 to exert classical apoptosis. Moreover, oxidative DNA damage leads to the release and nuclear truncation of mitochondrial apoptosis-inducing kinase, which triggers apoptosis-like programmed cell death via cyclophilin A. These observations could indicate crucial implications for oxidative stress in several steps of the pathomechanisms of neurodegenerative diseases.
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PMID:[The role for oxidative stress in neurodegenerative diseases]. 1830 64

The antiproliferative effects of 15-LOX (15-lipoxygenase) metabolites of arachidonic acid {(15S)-HPETE [(15S)-hydroperoxyeicosatetraenoic acid] and (15S)-HETE [(15S)-hydroxyeicosatetraenoic acid]} and the mechanism(s) involved were studied in the human T-cell leukaemia cell line Jurkat. (15S)-HPETE, the hydroperoxy metabolite of 15-LOX, inhibited the growth of Jurkat cells 3 h after exposure and with an IC(50) value of 10 microM. The hydroxy metabolite of 15-LOX, (15S)-HETE, on the other hand, inhibited the growth of Jurkat cells after 6 h of exposure and with an IC(50) value of 40 microM. The cells exposed to 10 microM (15S)-HPETE for 3 h or to 40 microM (15S)-HETE for 6 h showed increased expression of Fas ligand and FADD (Fas-associated death domain), caspase 8 activation, Bid (BH3-interacting domain death agonist) cleavage, decrease in mitochondrial membrane potential, cytochrome c release, caspase 3 activation, PARP-1 [poly(ADP-ribose) polymerase-1] cleavage and DNA fragmentation, suggesting the involvement of both extrinsic and intrinsic death pathways. Further studies on ROS (reactive oxygen species) generation revealed the involvement of NADPH oxidase. In conclusion, the present study indicates that NADPH oxidase-induced ROS generation activates the Fas-mediated death pathway.
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PMID:Effects of (15S)-hydroperoxyeicosatetraenoic acid and (15S)-hydroxyeicosatetraenoic acid on the acute- lymphoblastic-leukaemia cell line Jurkat: activation of the Fas-mediated death pathway. 1849 9


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