Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.2 (NQO1)
 6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enzymatically dissociated flexor digitorum brevis (FDB) and soleus fibres from mouse were used to compare the kinetics of electrically elicited Ca2+ transients of slow and fast skeletal muscle fibres, using the fast Ca2+ dye MagFluo4-AM, at 20-22 degrees C. For FDB two Ca2+ transient morphologies, types I (MT-I, 11 fibres, 19%) and II (MT-II, 47 fibres, 81%), were found, the kinetic parameters (amplitude, rise time, half width, decay time, and time constants of decay) being statistically different. For soleus (n = 20) only MT-I was found, with characteristics similar to MT-I from FDB. Correlations with histochemically determined mATPase, reduced nicotinamide adenine dinucleotide diaphorase and alpha-glycerophosphate dehydrogenase activities, as well as immunostaining and myosin heavy chain electrophoretic analysis of both muscles suggest that signals classified as MT-I may correspond to slow type I and fast IIA fibres while those classified as MT-II may correspond to fast IIX/D fibres. The results point to the importance of Ca2+ signaling for characterization of muscle fibres, but also to its possible role in determining fibre function.
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PMID:Different fibre populations distinguished by their calcium transient characteristics in enzymatically dissociated murine flexor digitorum brevis and soleus muscles. 1954 97

Idebenone has recently been investigated as a drug therapy for Leber's hereditary optic neuropathy (LHON), a rare genetic mitochondrial disease that causes rapid and progressive bilateral vision loss. Although several studies have shown that idebenone can promote vision recovery in patients with LHON, the evidence for the efficacy of idebenone is still limited. Idebenone failed to demonstrate superiority over placebo in the primary end-points of the only published randomised, double-blind, placebo-controlled trial. There appears to be a patient-specific response to idebenone with high variability in therapeutic outcomes. A recent study suggested that the cytosolic enzyme NAD(P)H: quinone acceptor oxidoreductase (NQO1) is the major enzyme involved in the activation of idebenone, and the beneficial effects of idebenone are dependent on the expression of NQO1. Here, we confirm the NQO1-dependent activity of idebenone, but we also show, for the first time, that the cytotoxicity of idebenone is linked to cellular expression of NQO1. Upon idebenone administration, cells deficient in NQO1 show a marked decrease in viability in comparison to NQO1 expressing cells, with idebenone causing ROS production and deleterious effects on ATP levels and cell viability. In addition, our data highlights that only cells expressing NQO1 can significantly activate idebenone, indicating that other proposed metabolic activation pathways, such as complex II and glycerol-3-phosphate dehydrogenase, do not play a significant role in idebenone activation. Furthermore, we provide evidence of idebenone-induced toxicity in the retina ex-vivo, which can be explained by the variation of NQO1 expression between different cell types in the mouse retina. Idebenone mediated cell rescue in the rotenone ex vivo model also indicated that this drug has a narrow therapeutic window. These findings will help to guide the development of future therapies and drug delivery strategies including intra-ocular administration. The specific dependence of idebenone activity on NQO1 may also explain the variation in patient outcomes in clinical trials.
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PMID:The ying and yang of idebenone: Not too little, not too much - cell death in NQO1 deficient cells and the mouse retina. 3177 23


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