Paul Schumacker

..We conclude that ROS can trigger preconditioning by causing activation of the K(ATP) channel, which then induces generation of ROS and NO that are both required for preconditioning protection...

..Below we will discuss the aspects of this novel model of O2 sensing and its applicability to the HPV response...

..Hence, genetic animal models are required to test mechanistic hypotheses...

..In this respect, it appears that tumor cells may die by the same systems they require...

..Although the specific targets of reactive oxygen species signals are not fully understood, this signaling pathway is critical for development and for normal lung responses in the newborn and the mature lung...

..This shift is mediated by an increase in cellular reactive oxygen species (ROS) generation that amplifies HIF-α stabilization and HIF-dependent gene expression, thereby driving the tumor phenotype...

..Therefore, differences in ROS production, HIF proliferation, and cell proliferation contribute to the differences in tumor phenotype in cells lacking SdhB as opposed to those lacking SdhA...

..show that SIRT3 functions as a tumor suppressor by enhancing the expression of mitochondrial MnSOD. Loss of SIRT3 leads to increased mitochondrial ROS, which then enhances cellular transformation and tumor growth...

..They suggest that 'permissive hypoxia' represents a therapeutic possibility. But before we turn down the inspired O2 levels we should consider the broader effects of hypoxia on tissue repair in critical illness...

..Recent studies have implicated mitochondrial reactive oxygen species (ROS) in regulating hypoxic pulmonary vasoconstriction (HPV), but controversy exists regarding whether hypoxia increases or decreases ROS generation...

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..These results demonstrate that hypoxia triggers increases in PASMC [Ca(2+)](i) by augmenting ROS signaling from the mitochondria...

..These findings provide genetic evidence that hypoxia utilizes mitochondrial ROS as signaling molecules to activate HIF-dependent extension of replicative life span...

..Taken together, our data demonstrate cooperation in signaling between Smad3 and HIF-1α and suggest a new paradigm in which HIF-1α is necessary for normoxic, TGF-β1-stimulated renal cell fibrogenesis...

..These data suggest that PDE5 expression and activity play a critical role in modulating neonatal pulmonary vascular tone in response to common clinical treatments for PPHN, such as oxygen and inhaled NO...

..g. 44% DLBCL vs. 11% of FL cases with moderate-to-high expression of HIF-1alpha and HIF-2alpha, P = 0.0017). These data demonstrate that HIF and the thioredoxin family are abnormally activated in lymphoma...

..Collectively, these results indicate that an increase in cytosolic ROS signaling is required for the increase in [Ca(2+)](i) in PASMCs in precision-cut mouse lung slices during the acute HPV response...

..This study establishes the potential of metabolic targeting as a broader means to kill and sensitize myeloma and identifies a compound that can achieve this goal...

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..Acute lung injury and the acute respiratory distress syndrome are characterized by increased lung oxidant stress and apoptotic cell death. The contribution of epithelial cell apoptosis to the development of lung injury is unknown...

..CONCLUSION The expression of HIF-1alpha protein is an important independent favorable prognostic factor for survival in patients with DLBCL treated with R-CHOP...

..We conclude that baseline PDE5 activity and oxidative stress is increased in PPHN PASMC, and scavenging H2O2 is sufficient to block oxidant-mediated increases in PDE5 activity in PPHN...

..Thus, the ROS signal is sustained during prolonged hypoxia in PASMCs and PAECs, and this is sufficient but not required for RhoA activation...

..Collectively, these results indicate a ROS-independent but p53/pRb-dependent senescence mechanism during hyperoxia...

..The sources of these oxidant signals are thought to include members of the NAD(P)H oxidase system and/or mitochondria. This article reviews evidence for and against the involvement of these systems in the O2 sensing pathway...

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..Consumers may take higher doses of dietary supplements in the belief that natural herbs have no major side effects. This study demonstrates that dosages of GSPE should be optimized to avoid potential harmful pro-oxidant effects...

..These results demonstrate that mitochondria function as O(2) sensors and signal hypoxic HIF-1 alpha and HIF-2 alpha stabilization by releasing ROS to the cytosol...

..However, recent developments in genetic techniques and redox-sensitive probes may allow us eventually to reach a consensus concerning the O(2) sensing mechanism underlying HPV...

..This article summarizes the potential involvement of a mitochondria-induced ROS signal in these two very different models...

..These findings indicate that the mitochondrial O2 sensing mechanism is highly conserved throughout evolution...

..Its effect does not require PKC, mito K(ATP) channel, or NO synthase, presumably because it acts by reactive oxygen species scavenging and iron chelating directly...

..This increase would then lead to the activation of an oxidant-sensitive signaling transduction pathway leading to HPV. This article summarizes the potential involvement of mitochondria in these two very different models...

..This has the advantage of avoiding possible side effects that may arise when higher doses of a single herb are used in an attempt to achieve a maximum degree of antioxidant activity...

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..We conclude that particulate matter air pollution induces the generation of ROS primarily from site III of the mitochondrial electron transport chain and that these ROS activate the intrinsic apoptotic pathway through ASK1, JNK, and p53...

..This result provided the molecular basis for the potent antiproliferative activity of this class of marine macrolides, thus identifying them as new biochemical tools for investigation of eukaryotic energy metabolism...

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..These findings reveal that, in isolated cardiomyocytes, sublethal H(2)O(2) generation during simulated ischemia regulates cell death during simulated reperfusion, which is mediated by the reperfusion oxidant burst...

..This response is associated with a remarkable attenuation of cell death, suggesting that ischemic cell death may be a regulated event...

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..These data point to the dynamic role played by hypoxia, associated with HIF-1 up-regulation, in promoting survival of cortical neurons, in part through stimulation of VEGF expression and release...

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..These findings indicate that mitochondrial oxidants generated in response to endothelial strain trigger FAK phosphorylation through a signaling pathway that involves PKC...

..These results provide genetic evidence indicating that mtROS act upstream of prolyl hydroxylases in regulating HIF-1 alpha and HIF-2 alpha in this O(2)-sensing pathway...

..Collectively, these studies identify a central role for mitochondrial ROS generation during ischemia in the mitochondrial depolarization and subsequent cell death induced by ischemia and reperfusion in this model...

..We conclude that AGBE is a potent antioxidant that protects cardiomyocytes against oxidant-mediated injury and this protection is partly mediated by its free radical scavenging properties...

..These findings demonstrate that mitochondria function as mechanotransducers in endothelium by increasing ROS signaling, which is required for strain-induced increase in VCAM-1 expression via NF-kappaB...

..We conclude that baicalein can scavenge ROS generation in cardiomyocytes and that it protects against cell death in an ischemia-reperfusion model when given only at reperfusion...

..Collectively, these studies will provide new information regarding the mechanisms of oxygen sensing in cells, which is important in normal tissues and in disease states. ..

..These studies will identify a novel pathway of cellular O2 detection, and may help clarify understanding of how cells adapt to lowered O2 conditions. ..

..Collectively, these studies will test whether a common O2 sensing mechanism functions in PA myocytes and endothelial cells to trigger their diverse responses in HPV. ..

..Collectively, these studies will provide a more conclusive test of the hypothesis that mitochondrial ROS are the site of 02 sensing responsible for HIF-1 activation and gene expression during hypoxia. ..

..Collectively, these studies could identify a novel mechanism of O2 sensing in the lung, and provide a mechanistic explanation for the activation of gene transcritpion and cellular proliferation during intermittent hypoxia. ..

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..This work will clarify and quantify the relationships among capillary surface area, microvascular flow heterogeneity, and the ability of tissues to maintain supply-independent VO2 in the face of limited O2 delivery...

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