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Resveratrol (trans-3,4V,5-trihydroxystilbene) is a naturally occurring polyphenolic compound highly enriched in grapes, peanuts, red wine, and a variety of food sources. Resveratrol has antiinflammatory and antioxidant properties, and also has potent anticancer properties. Human glioma U251 cells were used to understand the molecular mechanisms by which resveratrol acts as an anticancer agent, since glioma is a particularly difficult cancer to treat and eradicate. Our data show that resveratrol induces dose-and time-dependent death of U251 cells, as measured by lactate dehydrogenase release and internucleosomal DNA fragmentation assays. Resveratrol induces activation of caspase-3 and increases the cleavage of the downstream caspase substrate, poly(ADP-ribose) polymerase. Resveratrol-induced DNA fragmentation can be completely blocked by either a general caspase inhibitor (Z-VAD-FMK) or a selective caspase-3 inhibitor (Z-DEVD-FMK), but not by a selective caspase-1 inhibitor. Resveratrol induces cytochrome c release from mitochondria to the cytoplasm and activation of caspase-9. Resveratrol also increases expression of proapoptotic Bax and its translocation to the mitochondria. Resveratrol inhibits U251 proliferation, as measured by MTS assay [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt], and induces G 0 /G 1 growth arrest, as determined by flow cytometry. The cyclin-dependent kinase inhibitor, olomoucine, prevents cell cycle progression and resveratrol-induced apoptosis. These results suggest that multiple signaling pathways may underlie the apoptotic death of U251 glioma induced by resveratrol, which warrants further exploration as an anticancer agent in human glioma. [Mol Cancer Ther 2005;4(4):554 -61]

To understand the role of Ras-MAPK (mitogen-activated protein kinase) in trophic factor withdrawal- and oxidative stress-induced apoptotic cell death processes, undifferentiated rat pheochromocytoma PC12 cells and a PC12 variant cell line stably expressing the Ras dominant-negative mutant (M-M17-26) were subjected to serum withdrawal in the absence or presence of H2O2 treatment. The extent of cell death was analyzed by lactate dehydrogenase release, internucleosomal DNA fragmentation, and caspase-3 assays. Both serum withdrawal and H2O2 treatment induced apoptotic cell death in PC12 cells, and the extent of cell death was greatly enhanced in M-M17-26 cells. DNA fragmentation induced by serum withdrawal or H2O2 treatment was blocked completely by a general caspase inhibitor, Z-VAD-FMK. A selective MAPK kinase inhibitor, U0126, blocked the H2O2-induced phosphorylation of Erk1/2 (extracellular signal-regulated kinase) in PC12 cells and increased the levels of active caspase-3 in M-M17-26 under serum withdrawal or H2O2 treatment. In addition, the short-term H2O2 treatment (5-30 min) was sufficient to cause DNA fragmentation in M-M17-26 cells even though H2O2 was removed and cells were incubated in regular growth medium with complete serum for 24 h. However, similar, short-term H2O2 treatment of PC12 cells did not induce DNA fragmentation 24 h later. These results suggest that the Ras-Erk pathway is critical in mediating protection against apoptotic cell death induced by either trophic factor withdrawal or increased oxidative stress.

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Purpose To compare total colonic gas volume and segmental luminal distention according to patient position at CT colonography (CTC), and determine which two views should constitute the routine protocol. Methods Volumetric analysis was retrospectively performed on CTC examinations from 146 adults (mean age, 59.2 years; 81M/65F; mean BMI, 30.9) where supine, prone, and right lateral decubitus series were sequentially obtained using continuous low-pressure CO2 insufflation. Total colonic gas volumes were assessed using a novel automated volumetric tool. In addition, two radiologists scored distention by segment using a 4-point scale (4=Optimal/3=Adequate/2=Inadequate/1=Collapsed). Results Mean colonic gas volume (±SD) for supine, prone, and decubitus positioning was 1,617±567 ml, 1441±505 ml, and 1901±627 ml, respectively (p<0.001). Colonic volume was highest on the right lateral decubitus series in 73.3% (107/146) and lowest in 6.2% (9/146) of cases, whereas the prone series was highest in 0.7% (1/146) and lowest in 73.3% (107/146) of cases. Overall mean segmental reader scores and % inadequate/collapsed for supine, prone, and decubitus positions were 3.48/3.33/3.71, and 10.4%/12.1%/4.2%, respectively (p<0.001). The only mean segmental scores below 3.0 were the sigmoid on supine (2.68) and prone (2.58), compared with 3.23 on decubitus (p<0.001). Improvement in both decubitus and supine distention over prone increased further with increasing BMI (p<0.001). Conclusions The right lateral decubitus position consistently yields the best colonic distention at CTC, and significantly improves sigmoid evaluation. Prone distention was the worst, particularly as BMI increased. Routine supine and decubitus positioning should be considered for standard CTC protocols, particularly in obese individuals. Automated volumetric analysis provides for rapid objective assessment of colonic distention.