Energy dependence of restitution in the gastric mucosa

Cheng, Aaron M.; Morrison, Sarah W.; Yang, David; Hagen, Susan J.

doi:10.1152/ajpcell.2001.281.2.c430

Cited by 34 publications

(22 citation statements)

References 43 publications

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“…[31][32][33][34][35] Other recent studies using cell culture and tissue-based assays have also relied on NaN 3 to generate chemical hypoxia. 36,37 In addition to cytochrome oxidase, NaN 3 also inhibits nucleoside triphosphate diphosphohydrolase, an ecto-diphosphohydralase that hydrolyzes nucleosides extracellularly at pH 8. 38 Inflammatory cells with catalase and myeloperoxidase can oxidize NaN 3 to generate nitric oxide.…”

Section: Metabolic Inhibitorsmentioning

confidence: 99%

Glycolytic glioma cells with active glycogen synthase are sensitive to PTEN and inhibitors of PI3K and gluconeogenesis

Beckner

Gobbel

Abounader

et al. 2005

Laboratory Investigation

103

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Increased glycolysis is characteristic of malignancy. Previously, with a mitochondrial inhibitor, we demonstrated that glycolytic ATP production was sufficient to support migration of melanoma cells. Recently, we found that glycolytic enzymes were abundant and some were increased in pseudopodia formed by U87 glioma (astrocytoma) cells. In this study, we examined cell migration, adhesion (a step in migration), and Matrigel invasion of U87 and LN229 glioma cells when their mitochondria were inhibited with sodium azide or limited by 1% O 2 . Cell migration, adhesion, and invasion were comparable, with and without mitochondrial inhibition. Upon discovering that glycolysis alone can support glioma cell migration, unique features of glucose metabolism in astrocytic cells were investigated. The ability of astrocytic cells to remove lactate, the inhibitor of glycolysis, via gluconeogenesis and incorporation into glycogen led to consideration of supportive genetic mutations. Loss of phosphatase and tensin homolog (PTEN) releases glycogenesis from constitutive inhibition by glycogen synthase kinase-3 (GSK3). We hypothesize that glycolysis in gliomas can support invasive migration, especially when aided by loss of PTEN's regulation on the phosphatidylinositol-3 kinase (PI3K)/Akt pathway leading to inhibition of GSK3. Migration of PTEN-mutated U87 cells was studied for release of extracellular lactic acid and support by gluconeogenesis, loss of PTEN, and active PI3K. Lactic acid levels plateaued and phosphorylation changes confirmed activation of the PI3K/Akt pathway and glycogen synthase when cells relied only on glycolysis. Glycolytic U87 cell migration and phosphorylation of GSK3 were inhibited by PTEN transfection. Glycolytic migration was also suppressed by inhibiting PI3K and gluconeogenesis with wortmannin and metformin, respectively. These findings confirm that glycolytic glioma cells can migrate invasively and that the loss of PTEN is supportive, with activated glycogenic potential included among the relevant downstream effects.

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Section: Metabolic Inhibitorsmentioning

confidence: 99%

Glycolytic glioma cells with active glycogen synthase are sensitive to PTEN and inhibitors of PI3K and gluconeogenesis

Beckner

Gobbel

Abounader

et al. 2005

Laboratory Investigation

103

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“…However, the reductions in basal and histaminergenic gastric acid secretion of the SOD2-deficient mice were well in agreement with the extent to which mitochondrial ATP synthase was impaired. Gastric acid secretion is not only strictly dependent on ATP but is almost completely shut down by inhibition of oxidative phosphorylation in response to chemical anoxia (5,16). ATP depletion is a prominent feature underlying necrosis (51), so it is reasonable to infer that a compromised metabolic state would adversely impact the susceptibility to gastric mucosal injury.…”

Section: Discussionmentioning

confidence: 99%

Loss of parietal cell superoxide dismutase leads to gastric oxidative stress and increased injury susceptibility in mice

Jones

Zhu

Sarino

et al. 2011

American Journal of Physiology-Gastrointestinal and Liver Physi

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Jones MK, Zhu E, Sarino EV, Padilla OR, Takahashi T, Shimizu T, Shirasawa T. Loss of parietal cell superoxide dismutase leads to gastric oxidative stress and increased injury susceptibility in mice. Am J Physiol Gastrointest Liver Physiol 301: G537-G546, 2011. First published June 30, 2011 doi:10.1152/ajpgi.00177.2011Mitochondrial superoxide dismutase (SOD2) prevents accumulation of the superoxide that arises as a consequence of oxidative phosphorylation. However, SOD2 is a target of oxidative/nitrosative inactivation, and reduced SOD2 activity has been demonstrated to contribute to portal hypertensive gastropathy. We investigated the consequences of gastric parietal cell-specific SOD2 deficiency on mitochondrial function and gastric injury susceptibility. Mice expressing Cre recombinase under control of the parietal cell Atpase4b gene promoter were crossed with mice harboring loxP sequences flanking the sod2 gene (SOD2 floxed mice). Cre-positive mice and Cre-negative littermates (controls) were used in studies of SOD2 expression, parietal cell function (ATP synthesis, acid secretion, and mitochondrial enzymatic activity), increased oxidative/nitrosative stress, and gastric susceptibility to acute injury. Parietal cell SOD2 deficiency was accompanied by a 20% (P Ͻ 0.05) reduction in total gastric SOD activity and a 93% (P Ͻ 0.001) reduction in gastric SOD2 activity. In SOD2-deficient mice, mitochondrial aconitase and ATP synthase activities were impaired by 36% (P Ͻ 0.0001) and 44% (P Ͻ 0.005), respectively. Gastric tissue ATP content was reduced by 34% (P Ͻ 0.002). Basal acid secretion and peak secretagogue (histamine)-induced acid secretion were reduced by 43% (P Ͻ 0.0001) and 40% (P Ͻ 0.0005), respectively. There was a fourfold (P Ͻ 0.02) increase in gastric mucosal apoptosis and 41% (P Ͻ 0.001) greater alcohol-induced gastric damage in the parietal cell SOD2-deficient mice. Our findings indicate that loss of parietal cell SOD2 leads to mitochondrial dysfunction, resulting in perturbed energy metabolism, impaired parietal cell function, and increased gastric mucosal oxidative stress. These alterations render the gastric mucosa significantly more susceptible to acute injury.

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“…The parietal cells of the gastric mucosa are primarily responsible for the secretion of acid to aid in digestion, and are dependent on ATP generated by the mitochondria for proper function (14,38). Parietal cell loss and increased oxidant damage has been shown to play a role in gastric diseases such as gastric hypertensive gastropathy (1,52).…”

Section: Mammary Glandmentioning

confidence: 99%

The Use of the Cre/loxPSystem to Study Oxidative Stress in Tissue-Specific Manganese Superoxide Dismutase Knockout Models

Marecki

Parajuli

Crow

et al. 2014

Antioxidants & Redox Signaling

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Significance: Respiring mitochondria are a significant site for reactions involving reactive oxygen and nitrogen species that contribute to irreversible cellular, structural, and functional damage leading to multiple pathological conditions. Manganese superoxide dismutase (MnSOD) is a critical component of the antioxidant system tasked with protecting the oxidant-sensitive mitochondrial compartment from oxidative stress. Since global knockout of MnSOD results in significant cardiac and neuronal damage leading to early postnatal lethality, this approach has limited use for studying the mechanisms of oxidant stress and the development of disease in specific tissues lacking MnSOD. To circumvent this problem, a number of investigators have employed the Cre/loxP system to precisely knockout MnSOD in individual tissues. Recent Advances: Multiple tissue and organ-specific Creexpressing mice have been generated, which greatly enhance the specificity of MnSOD knockout in tissues and organ systems that were once difficult, if not impossible to study. Critical Issues: Evaluating the contribution of MnSOD deficiency to oxidant-mediated mitochondrial damage requires careful consideration of the promoter system used for creating the tissue-specific knockout animal, in addition to the collection and interpretation of multiple indices of oxidative stress and damage. Future Directions: Expanded use of well-characterized tissuespecific promoter elements and inducible systems to drive the Cre/loxP recombinational events will lead to a spectrum of MnSOD tissue knockout models, and a clearer understanding of the role of MnSOD in preventing mitochondrial dysfunction in human disease.

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Energy dependence of restitution in the gastric mucosa

Cited by 34 publications

References 43 publications

Glycolytic glioma cells with active glycogen synthase are sensitive to PTEN and inhibitors of PI3K and gluconeogenesis

Glycolytic glioma cells with active glycogen synthase are sensitive to PTEN and inhibitors of PI3K and gluconeogenesis

Loss of parietal cell superoxide dismutase leads to gastric oxidative stress and increased injury susceptibility in mice

The Use of the Cre/loxPSystem to Study Oxidative Stress in Tissue-Specific Manganese Superoxide Dismutase Knockout Models

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