Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.99.6 (NADPH oxidase)
 10,295 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The majority of physiological processes proceed most favourably when O(2) is in plentiful supply. However, there are a number of physiological and pathological circumstances in which this supply is reduced either acutely or chronically. A crucial homeostatic response to such arterial hypoxaemia is carotid body excitation and a resultant increase in ventilation. Central to this response in carotid body, and many other chemosensory tissues, is the rapid inhibition of ion channels by hypoxia. Since the first direct demonstration of hypoxia-evoked depression in K(+) channel activity, the numbers of mechanisms which have been proposed to serve as the primary O(2) sensor have been almost as numerous as the experimental strategies with which to probe their nature. Three of the current favourite candidate mechanisms are mitochondria, AMP-activated kinase and haemoxygenase-2; a fourth proposal has been NADPH oxidase, but recent evidence suggests that this enzyme plays a secondary role in the O(2)-sensing process. All of these proposals have attractive points, but none can fully reconcile all of the data which have accumulated over the last two decades or so, suggesting that there may, in fact, not be a unique sensing system even within a single cell type. This latter point is key, because it implies that the ability of a cell to respond appropriately to decreased O(2) availability is biologically so important that several mechanisms have evolved to ensure that cellular function is never compromised during moderate to severe hypoxic insult.
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PMID:Detecting acute changes in oxygen: will the real sensor please stand up? 1685 17

Activation of AMP-activated kinase (AMPK) suppresses NF-kappaB-mediated transcription in endothelial cells exposed to palmitate or TNF-alpha; it also impedes angiotensin II-driven proliferation in vascular smooth muscle cells. These phenomena become predictable if we postulate that AMPK can inhibit activation of NADPH oxidase. Such an effect would make sense from a homeostatic perspective, and moreover there is direct evidence that AMPK suppresses NADPH oxidase activation in neutrophils. New evidence that sub-pathological levels of peroxynitrite can activate AMPK suggest that this enzyme may act as an "early warning signal" for oxidant stress; inhibiting NADPH oxidase would constitute a rational feedback response to such a signal.
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PMID:AMP-activated kinase may suppress NADPH oxidase activation in vascular tissues. 1918 55

Over the last 20 years, it has been shown that complex signaling cascades are involved in zinc excitotoxicity. Free zinc rapidly induces PKC activation, which causes reactive oxygen species (ROS) production at least in part through NADPH oxidase. It also promotes neuronal nitric oxide synthase, thereby increasing nitric oxide (NO) production. Extracellular signal-regulated kinase activation and Egr-1 transcription factor activity were quickly induced by zinc, too. These concurrent actions of kinases consequently produce oxygen free radical, ROS, and NO, which may cause severe DNA damage. Following the excessive activity of poly(ADP-ribose) polymerase-1 depletes NAD+/ATP in the cells. Zinc excitotoxicity exhibits distinct characteristics of apoptosis, too. Activation of caspase-3 is induced by liver kinase B1 (LKB1)-AMP-activated kinase (AMPK)-Bim cascade signaling and induction of p75NTR receptors and p75NTR-associated Death Executor. Thus, zinc excitotoxicity is a mechanism of neuronal cell death showing various cell death patterns. In addition to the above signaling cascades, individual intracellular organelles also play a crucial role in zinc excitotoxicity. Mitochondria and lysosomes function as zinc reservoirs, and as such, are capable of regulating zinc concentration in the cytoplasm. However, when loaded with too much zinc, they may undergo mitochondrial permeability transition pore (mPTP) opening, and lysosomal membrane permeabilization (LMP), both of which are well-established mechanisms of cell death. Since zinc excitotoxicity has been reported to be associated with acute brain injuries, including stroke, trauma, and epilepsy, we performed to find the novel AMPK inhibitors as therapeutic agents for these diseases. Since we thought acute brain injury has complicated neuronal death pathways, we tried to see the neuroprotection against zinc excitotoxicity, calcium-overload excitotoxicity, oxidative damage, and apoptosis. We found that two chemicals showed significant neuroprotection against all cellular neurotoxic models we tested. Finally, we observed the reduction of infarct volume in a rat model of brain injury after middle cerebral artery occlusion (MCAO). In this review, we introduced the AMPK-mediated cell death mechanism and novel strategy for the development of stroke therapeutics. The hope is that this understanding would provide a rationale for acute brain injury and eventually find new therapeutics.
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PMID:Mechanism of Zinc Excitotoxicity: A Focus on AMPK. 3304 69