NF-κB Inhibition Enhances Peroxynitrite-Induced Enterocyte Apoptosis

Potoka, Douglas A.; Upperman, Jeffrey S.; Nadler, Evan P.; Wong, C.; Zhou, Xin; Zhang, Xiao Ru; Ford, Henri R.

doi:10.1006/jsre.2002.6423

Cited by 33 publications

(28 citation statements)

References 49 publications

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“…BCL-2 remains the prototypic antiapoptotic protein and the data are less clear as to whether NF-kB regulates its transcription. There are reports of activation or inhibition as well as reports demonstrating no NF-kB-dependent transcriptional effect in the BCL-2 promoter (Sohur et al, 1999;Catz and Johnson, 2001;Potoka et al, 2002). In pancreatic cancer, BCL-2 is frequently overexpressed and its overexpression confers chemo-and radioresistance and enhances tumorigenic and metastatic capability (Bold et al, 1999a, b;Nio et al, 2001;Su et al, 2001).…”

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confidence: 99%

AKT inhibition is associated with chemosensitisation in the pancreatic cancer cell line MIA-PaCa-2

et al. 2003

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Activation of the serine/threonine kinase AKT is common in pancreatic cancer; inhibition of which sensitises cells to the apoptotic effect of chemotherapy. Of the various downstream targets of AKT, we examined activation of the NF-kB transcription factor and subsequent transcriptional regulation of BCL-2 gene family in pancreatic cancer cells. Inhibition of either phosphatidylinositol-3 kinase or AKT led to a decreased protein level of the antiapoptotic gene BCL-2 and an increased protein level of the proapoptotic gene BAX. Furthermore, inhibition of AKT decreased the function of NF-kB, which is capable of transcriptional regulation of the BCL-2 gene. Inhibiting this pathway had little effect on the basal level of apoptosis in pancreatic cancer cells, but increased the apoptotic effect of chemotherapy. The antiapoptotic effect of AKT activation in pancreatic cancer cells may involve transcriptional induction of a profile of BCL-2 proteins that confer resistance to apoptosis; alteration of this balance allows sensitisation to the apoptotic effect of chemotherapy.

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confidence: 99%

AKT inhibition is associated with chemosensitisation in the pancreatic cancer cell line MIA-PaCa-2

et al. 2003

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“…Peroxynitrite, a metabolite formed by the reaction of NO and superoxide, has been shown to play an important role in inducing apoptosis in a variety of cell types [40][41][42][43] . Peroxynitrite induces apoptosis through the activation of procaspase 9, which in turn activates other downstream effector caspases [44,45] . Peroxynitrite plays an in important role in the cellular damage associated with the overproduction of NO.…”

Section: Discussionmentioning

confidence: 99%

Exogenous Superoxide Dismutase Prevents Peroxynitrite-Induced Apoptosis in Non-Heart-Beating Donor Livers

et al. 2008

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Objective: To investigate the role of oxygen free radicals in the induction of apoptosis in non-heart-beating donor (NHBD) livers, and if superoxide dismutase (SOD) ameliorates these alterations. Methods: Rat livers were perfused via the portal vein with histidine/tryptophan/α-ketoglutarate solution from heart-beating donors (HBD) or 60-min warm ischemia from NHBD, with or without the addition of SOD. After 24 h, cold storage livers were evaluated by isolated reperfusion. Results: NHBD showed significantly higher enzyme leakage and elevated portal venous pressure (PVP) versus HBD. Bile and total adenine nucleotides (TAN) were significantly decreased. Apoptosis was prominent in sinusoidal lining cells, coupled with strong nitrotyrosine staining (NTR). The concentrations of nitric oxide and lipoperoxides were largely increased. SOD medication reduced hepatic enzyme release by 30% and lipoperoxides by nearly 50%. Apoptosis and NTR were significantly decreased, and PVP was strikingly reduced to normal values. A 3-fold enhancement in bile production and 1.5-fold increase in TAN of the liver tissue were also observed. Conclusion: NHBD livers are prone to severe reoxygenation injury promoted by oxygen free radicals, massive nitrite oxide production and peroxynitrite-induced apoptosis within the sinusoids. Antioxidant medication with SOD should be considered as a useful means of preserving NHBD livers.

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“…NF-B activates the transcription of many genes involved in the infl ammatory process [32,33,35] . Under resting conditions, NF-B exists in an inactive form in the cytoplasm of cells.…”

Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Reduces Hepatic Sequelae in Experimental Necrotizing Enterocolitis

Halpern¹,

Holubec²,

Clark³

et al. 2006

Neonatology

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Background and Aim: Neonatal necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of premature infants. We recently demonstrated that the gut/liver axis plays an important role in the pathophysiology of NEC through the release of inflammatory mediators into the intestinal lumen. We have also shown that supplementation of formula with epidermal growth factor (EGF) dramatically decreases ileal pathology associated with experimental NEC. In this study, we examined the effects of EGF on the liver portion of the gut/liver axis in the neonatal rat model of NEC. Methods: Newborn rats were divided into three experimental groups, NEC, hand-fed with growth-factor free formula; NEC + EGF, hand-fed with formula supplemented with 500 ng/ml rat EGF; or DF, dam fed. All animals were exposed to asphyxia and cold stress twice daily for 4 days to develop NEC. Results: EGF receptor expression was significantly (p ≤ 0.01) decreased in the NEC + EGF group compared to the NEC group. EGF supplementation significantly decreased Kupffer cell numbers (p ≤ 0.01) as well as hepatic tumor necrosis factor (TNF)-α and interleukin-18 production (p ≤ 0.05). Further, TNF-α in the intestinal luminal contents of the NEC + EGF group were normalized to levels observed in DF controls compared to the NEC group (p ≤ 0.05). Activated nuclear factor-ĸB was also substantially decreased in the NEC + EGF group versus the NEC group. Conclusion: The results of this study indicate that EGF normalizes cytokine overproduction in the liver of neonatal rats with NEC, which contributes to diminished intestinal damage during the development of experimental NEC. These data suggest that supplementation of formula with EGF can have beneficial effects on the gut/liver axis during NEC pathogenesis.

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NF-κB Inhibition Enhances Peroxynitrite-Induced Enterocyte Apoptosis

Cited by 33 publications

References 49 publications

AKT inhibition is associated with chemosensitisation in the pancreatic cancer cell line MIA-PaCa-2

AKT inhibition is associated with chemosensitisation in the pancreatic cancer cell line MIA-PaCa-2

Exogenous Superoxide Dismutase Prevents Peroxynitrite-Induced Apoptosis in Non-Heart-Beating Donor Livers

Epidermal Growth Factor Reduces Hepatic Sequelae in Experimental Necrotizing Enterocolitis

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