No abstract

Both pro-and antiapoptotic activities of NF-B transcription factor have been observed; however, less is known about the mechanism by which NF-B induces apoptosis. To elucidate how NF-B regulates proapoptotic signaling, we performed functional analyses using wild-type, ikk1؊/؊ , ikk2 ؊/؊ , rela ؊/؊ murine fibroblasts, MDAPanc-28/Puro, MDAPanc-28/IB␣M, and HCT116/p53 ؉/؉ and HCT116/p53 ؊/؊ cells with investigational anticancer agent doxycycline as a superoxide inducer for generating apoptotic stimulus. In this report, we show that doxycycline increased superoxide generation and subsequently activated NF-B, which in turn up-regulated p53 expression and increased the stability and DNA binding activity of p53. Consequently, NF-Bdependent p53 activity induced the expression of p53-regulated genes PUMA and p21 waf1 as well as apoptosis. Importantly, lack of RelA, IKK, and p53 as well as expression of a dominant negative IB␣ (IB␣M) inhibited NF-B-dependent p53 activation and apoptosis. The doxycycline-induced NF-B activation was not inhibited in HCT116/p53 ؊/؊ cells. Our results demonstrate that NF-B plays an essential role in activation of wild-type p53 tumor suppressor to initiate proapoptotic signaling in response to overgeneration of superoxide. Thus, these findings reveal a mechanism of NF-B-regulated proapoptotic signaling.

We investigated the early postnatal changes of the mesenteric circulation and its relation to the systemic circulation in 15 preterm infants. The infants were studied before the first feeding on d 1 and pre- and postprandially on d 3, 4, 5, and 7. Blood flow velocity was measured by ultrasound Doppler in the superior mesenteric artery, middle cerebral artery, and the aortic orifice for cardiac output calculations. Blood pressure and heart rate were monitored. From d 1 to d 3, the preprandial stroke volume decreased [1.5 +/- 0.3 to 1.3 +/- 0.2 mL/kg (mean +/- SD), p < 0.05], whereas blood pressure (36 +/- 3 to 50 +/- 7 mm Hg, p < 0.001), superior mesenteric artery mean velocity (Vmean) (0.17 +/- 0.08 to 0.30 +/- 0.11 m/s, p < 0.05), and middle cerebral artery Vmean increased (0.15 +/- 0.05 to 0.22 +/- 0.03 m/s, p < 0.001). From d 3 through d 7, the preterm infants demonstrated higher preprandial end diastolic flow velocity in the superior mesenteric artery than we previously reported in term infants (0.15 +/- 0.05 versus 0.12 +/- 0.04, p < 0.05). Like the term infants, preterm infants increased their superior mesenteric artery Vmean by 83% postprandially and maintained a stable cerebral circulation with feeding. Unlike the term infants, feeding in the preterm infants induced a blood pressure decrease (51 +/- 6 to 48 +/- 6 mm Hg, p < 0.01) and a cardiac output increase (176 +/- 30 to 188 +/- 32 mL/kg/min, p < 0.001). These findings suggest that, in contrast to term infants, healthy preterm infants require compensatory systemic hemodynamic changes in response to feeding.