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101.
Although aberrant DNA methylation is considered to be one of the key ways by which tumor-suppressor and DNA-repair genes are silenced during tumor initiation and progression, the mechanisms underlying DNA methylation alterations in cancer remain unclear. Here we show that prostaglandin E(2) (PGE(2)) silences certain tumor-suppressor and DNA-repair genes through DNA methylation to promote tumor growth. These findings uncover a previously unrecognized role for PGE(2) in the promotion of tumor progression. 相似文献
102.
Cytochrome P-450 arachidonic acid epoxygenase. Regulatory control of the renal epoxygenase by dietary salt loading. 总被引:5,自引:0,他引:5
J H Capdevila S Wei J Yan A Karara H R Jacobson J R Falck F P Guengerich R N DuBois 《The Journal of biological chemistry》1992,267(30):21720-21726
The rat kidney microsomal epoxygenase catalyzed the asymmetric epoxidation of arachidonic acid to generate as major products: 8(R),9(S)-, 11(R),12(S)- and 14(S),15(R)-epoxyeicosatrienoic acids with optical purities of 97, 88, and 70%, respectively. Inhibition studies utilizing a panel of polyclonal antibodies to several rat liver cytochrome P-450 isoforms, indicated that the renal epoxygenase(s) belongs to the cytochrome P-450 2C gene family. Dietary salt, administered either as a 2-2.5% (w/v) solution in the drinking water or as a modified solid diet containing 8% NaCl (w/w), resulted in marked and selective increases in the renal microsomal epoxygenase activity (416 and 260% of controls, for the liquid and solid forms of NaCl, respectively) with no significant changes in the microsomal omega/omega-1 oxygenase or in the hepatic arachidonic acid monooxygenase reaction. Immunoblotting studies demonstrated that dietary salt induced marked increases in the concentration of a cytochrome P-450 isoform(s) recognized by polyclonal antibodies raised against human liver cytochrome P-450 2C10 or rat liver cytochrome P-450 2C11. Comparisons of the stereochemical selectivity of the induced and non-induced microsomal epoxygenase(s) with that of purified rat liver cytochrome P-450 2C11 suggest that the salt-induced protein(s) is catalytically and structurally different from liver cytochrome P-450 2C11. The in vivo significance of dietary salt in regulating the activities of the kidney endogenous arachidonic acid epoxygenase was established by the demonstration of a salt-induced 10-20-fold increase in the urinary output of epoxygenase metabolites. These results, in conjunction with published evidence demonstrating the potent biological activities of its metabolites, suggest a role for the epoxygenase in the renal response to dietary salt. 相似文献
103.
Backlund MG Mann JR Holla VR Buchanan FG Tai HH Musiek ES Milne GL Katkuri S DuBois RN 《The Journal of biological chemistry》2005,280(5):3217-3223
Prostaglandin E2 (PGE2) can stimulate tumor progression by modulating several proneoplastic pathways, including proliferation, angiogenesis, cell migration, invasion, and apoptosis. Although steady-state tissue levels of PGE2 stem from relative rates of biosynthesis and breakdown, most reports examining PGE2 have focused solely on the cyclooxygenase-dependent formation of this bioactive lipid. Enzymatic degradation of PGE2 involves the NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). The present study examined a range of normal tissues in the human and mouse and found high levels of 15-PGDH in the large intestine. By contrast, the expression of 15-PGDH is decreased in several colorectal carcinoma cell lines and in other human malignancies such as breast and lung carcinomas. Consistent with these findings, we observe diminished 15-Pgdh expression in ApcMin+/- mouse adenomas. Enzymatic activity of 15-PGDH correlates with expression levels and the genetic disruption of 15-Pgdh completely blocks production of the urinary PGE2 metabolite. Finally, 15-PGDH expression and activity are significantly down-regulated in human colorectal carcinomas relative to matched normal tissue. In summary, these results suggest a novel tumor suppressive role for 15-PGDH due to loss of expression during colorectal tumor progression. 相似文献
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Sheng H Shao J Washington MK DuBois RN 《The Journal of biological chemistry》2001,276(21):18075-18081
Chronic use of nonsteroidal anti-inflammatory drugs results in a significant reduction of risk and mortality from colorectal cancer in humans. All of the mechanism(s) by which nonsteroidal anti-inflammatory drugs exert their protective effects are not completely understood, but they are known to inhibit cyclooxygenase activity. The cyclooxygenase enzymes catalyze a key reaction in the conversion of arachidonic acid to prostaglandins, such as prostaglandin E(2) (PGE(2)). Here we demonstrate that PGE(2) treatment of LS-174 human colorectal carcinoma cells leads to increased motility and changes in cell shape. The prostaglandin EP(4) receptor signaling pathway appears to play a role in transducing signals which regulate these effects. PGE(2) treatment results in an activation of phosphatidylinositol 3-kinase/protein kinase B pathway that is required for the PGE(2)-induced changes in carcinoma cell motility and colony morphology. Our results suggest that PGE(2) might enhance the invasive potential of colorectal carcinoma cells via activation of major intracellular signal transduction pathways not previously reported to be regulated by prostaglandins. 相似文献
106.
Rats, when injected with endotoxin, begin to exhale nitric oxide (NO) within 1 h. This study measured the diffusing capacity for NO in the lungs of rats (DL(NO)) under both control and endotoxemic conditions, and it also estimated the rate at which endogenous NO (VP(NO)) enters the distal compartment of the lung, both in control rats and during endotoxemia. DL(NO) increased from 0.68 +/- 0.12 (SE) ml. min(-1). mmHg(-1) in control rats to 1.17 +/- 0.25 ml. min(-1). mmHg(-1) in endotoxemic rats. VP(NO) was 2.6 +/- 0.5 nl/min in control rats and attained a value of 218.6 +/- 50.1 nl/min at the height of NO exhalation 3 h after the endotoxin. We suggest that increased DL(NO) reflects an increase in pulmonary membrane diffusing capacity, caused by a pulmonary hypertension that is due to neutrophil aggregation in the lung capillaries. DL(NO) may also be increased by an enlarged pulmonary capillary volume because of the vasodilatory effects of the endogenous NO that is produced by the lung in response to the endotoxin. NO production by the lungs in response to endotoxin is unique in that it is the only situation reported to date in which pathologically induced increases in NO exhalation originate from the alveolar compartment of the lung, as opposed to the small conducting airways. 相似文献
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Clara Belzer Georg K. Gerber Guus Roeselers Mary Delaney Andrea DuBois Qing Liu Vera Belavusava Vladimir Yeliseyev Andres Houseman Andrew Onderdonk Colleen Cavanaugh Lynn Bry 《PloS one》2014,9(7)
Longitudinal studies of the microbiota are important for discovering changes in microbial communities that affect the host. The complexity of these ecosystems requires rigorous integrated experimental and computational methods to identify temporal signatures that promote physiologic or pathophysiologic responses in vivo. Employing a murine model of infectious colitis with the pathogen Citrobacter rodentium, we generated a 2-month time-series of 16S rDNA gene profiles, and quantitatively cultured commensals, from multiple intestinal sites in infected and uninfected mice. We developed a computational framework to discover time-varying signatures for individual taxa, and to automatically group signatures to identify microbial sub-communities within the larger gut ecosystem that demonstrate common behaviors. Application of this model to the 16S rDNA dataset revealed dynamic alterations in the microbiota at multiple levels of resolution, from effects on systems-level metrics to changes across anatomic sites for individual taxa and species. These analyses revealed unique, time-dependent microbial signatures associated with host responses at different stages of colitis. Signatures included a Mucispirillum OTU associated with early disruption of the colonic surface mucus layer, prior to the onset of symptomatic colitis, and members of the Clostridiales and Lactobacillales that increased with successful resolution of inflammation, after clearance of the pathogen. Quantitative culture data validated findings for predominant species, further refining and strengthening model predictions. These findings provide new insights into the complex behaviors found within host ecosystems, and define several time-dependent microbial signatures that may be leveraged in studies of other infectious or inflammatory conditions. 相似文献