Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, our laboratory reported that lactosylceramide (LacCer) stimulated human aortic smooth muscle cell proliferation via specific activation of p44 mitogen-activated protein kinase (MAPK) in the p21(ras)/Raf-1/MEK2 pathway and induced expression of the transcription factor c-fos downstream to the p44 MAPK signaling cascade (Bhunia A. K., Han, H., Snowden, A., and Chatterjee S. (1996) J. Biol. Chem. 271, 10660-10666). In the present study, we explored the role of free oxygen radicals in LacCer-mediated induction of cell proliferation. Superoxide levels were measured by the lucigenin chemiluminescence method, MAPK activity was measured by immunocomplex kinase assays, and Western blot analysis and c-fos expression were measured by Northern blot assay. We found that LacCer (10 microM) stimulates endogenous superoxide production (7-fold compared with control) in human aortic smooth muscle cells specifically by activating membrane-associated NADPH oxidase, but not NADH or xanthine oxidase. This process was inhibited by an inhibitor of NADPH oxidase, diphenylene iodonium (DPI), and by antioxidants, N-acetyl-L-cysteine (NAC) or pyrrolidine dithiocarbamate. NAC and DPI both abrogated individual steps in the signaling pathway leading to cell proliferation. For example, the p21(ras).GTP loading, p44 MAPK activity, and induction of transcription factor c-fos all were inhibited by NAC and DPI as well as an antioxidant pyrrolidine dithiocarbamate or reduced glutathione (GSH). In contrast, depletion of GSH by L-buthionine (S, R)-sulfoximine up-regulated the above described signaling cascade. In sum, LacCer, by virtue of activating NADPH oxidase, produces superoxide (a redox stress signaling molecule), which mediates cell proliferation via activation of the kinase cascade. Our findings may explain the potential role of LacCer in the pathogenesis of atherosclerosis involving the proliferation of aortic smooth muscle cells.
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PMID:Redox-regulated signaling by lactosylceramide in the proliferation of human aortic smooth muscle cells. 918 53

Pentagalloylglucose (5GG) is a potent and specific inhibitor of NADPH dehydrogenase or xanthine oxidase. In our previous study, we showed that 5GG was able to induce apoptosis in HL-60 cells in a time- and concentration-dependent manner via the activation of caspase-3. Recently, we found that 5GG was capable of perturbing the cell cycle of the human breast cancer cell line MCF-7. DNA flow cytometric analysis showed that 5GG exhibited the ability of blocking MCF-7 cell cycle progression at the G1 phase. The level of several G1 phase-related cyclins and cyclin-dependent kinases did not change in these cells during a 24-hr exposure to 5GG. However, the activity of cyclin E/CDK2 was decreased in a concentration- and time-dependent manner and the activity of cyclin D/CDK4 was inhibited when serum-starved synchronized cells were released from synchronization. p27(Kip) and p21(Cip), inhibitors of cyclin/CDK complexes in G1-phase, were gradually increased after 5GG treatment in a time-dependent manner and the induction of p21(Cip) was correlated with an increase in p53 levels. These results suggest that the suppression of cell-cycle progression in the G1 phase by 5GG was mediated in MCF-7 cells, at least in part, by either the inhibition of cyclin D/CDK4 and cyclin E/CDK2 activity or the induction of the CDK inhibitors p27(Kip) and p21(Cip).
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PMID:Induction of G1 phase arrest in MCF human breast cancer cells by pentagalloylglucose through the down-regulation of CDK4 and CDK2 activities and up-regulation of the CDK inhibitors p27(Kip) and p21(Cip). 1278 29

While some authors suggest that retinoids are potential anti-proliferative and antioxidant agents, evidence has suggested those present pro-oxidant properties, which might lead to malignant proliferation. These discordances stimulated one to investigate the proliferative/anti-proliferative properties of two major retinoids, retinol (ROH) and retinoic acid (RA). In Sertoli cells, ROH increased proliferation while RA was anti-proliferative. ROH increased DNA synthesis, decreased p21 levels and induced cell cycle progression. ROH increased reactive species (RS) production and stimulated p38, JNK1/2 and ERK1/2 MAPKs activation. Antioxidant treatment with Trolox blocked ROH-induced RS production, MAPKs activation and proliferation; MAPKs inhibition blocked proliferation. The potential sites of RS indicate that ROH-induced RS is promoted via mitochondria and xanthine oxidase. In contrast, RA induced neither RS production nor MAPKs activation. RA decreased DNA synthesis and increased p21 leading to cell arrest. Overall, data show that ROH, but not RA, is able to induce proliferation through non-classical and redox-dependent mechanisms.
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PMID:Differential effects of retinol and retinoic acid on cell proliferation: a role for reactive species and redox-dependent mechanisms in retinol supplementation. 1878 48

We hypothesize that nitroglycerin (NTG) causes direct oxidation of multiple cellular sulfhydryl (SH) proteins and that manipulation of SH redox status affects NTG tolerance. In LLC-PK1 cells, we found that nitrate tolerance, as indicated by cGMP accumulation toward NTG, was accompanied by increased protein [(35)S]cysteine incorporation, significant S-glutathionylation of multiple proteins, and decreased metabolic activity of several SH-sensitive enzymes, including creatine kinase, xanthine oxidoreductase, and glutaredoxin (GRX). Cells overexpressing GRX exhibited reduced cellular protein S-glutathionylation (PSSG) and absence of NTG tolerance, whereas those with silenced GRX showed increased extent of NTG-induced tolerance. Incubation of LLC-PK1 cells with oxidized glutathione led to several major observations associated with nitrate tolerance, namely, reduced cGMP accumulation, PSSG formation, superoxide accumulation, and the attenuation of these events by vitamin C. Aortic S-glutathionylated proteins increased approximately 3-fold in rats made tolerant in vivo to NTG and showed significant negative correlation with vascular responsiveness ex vivo. NTG incubation in EA.hy926 endothelial cells and LLC-PK1 cells led to increased S-glutathionylation and activity of p21(ras), a known mediator of cellular signaling. These results indicate that the hallmark events of NTG tolerance, such as reduced bioactivation and redox signaling, are associated with GRX-dependent protein deglutathionylation.
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PMID:Role of glutaredoxin-mediated protein S-glutathionylation in cellular nitroglycerin tolerance. 1922 66