Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that nitric oxide synthase (NOS), the enzyme that catalyzes the formation of nitric oxide (NO), is expressed in skeletal muscle. The aim of the present study was to test the hypothesis that NO can modulate glucose metabolism in slow- and fast-twitch skeletal muscles. Calcium-dependent NOS was detected in skeletal muscle, and the enzyme activity was greater in fast-type extensor digitorum longus (EDL) muscles than in slow-type soleus muscles. Both the neuronal-type (nNOS) and endothelial-type (eNOS) enzymes are expressed in resting skeletal muscles. However, nNOS protein was only detected in EDL muscles, whereas eNOS protein contents were comparable in soleus and EDL muscles. NOS expression in muscle cryosections (diaphorase histochemistry) was located in vascular endothelium and in muscle fibers, and the staining was greater in type IIb than in type I and IIa fibers. The macrophage-type inducible NOS (iNOS) was not detected in resting muscle, but endotoxin treatment induced its expression, concomitant with elevated NO production. iNOS induction was associated with impaired insulin-stimulated glucose uptake in isolated rat muscles. In vitro, NOS blockade with specific inhibitors did not affect basal or insulin-stimulated glucose transport in EDL or soleus muscles. In contrast, the NO donors GEA 5024 and sodium nitroprusside induced dose-dependent inhibition (up to 50%) of maximal insulin-stimulated glucose transport in both muscles with minor effects on basal uptake values. GEA 5024 also blunted insulin-stimulated glucose transport and amino acid uptake in cultured L6 muscle cells without affecting insulin binding to its receptor. On the other hand, the permeable cGMP analogue dibutyryl cGMP did not affect muscle glucose transport. These results strongly suggest that NO modulates insulin action in both slow- and fast-type skeletal muscles. This novel autocrine action of NO in muscle appears to be mediated by cGMP-independent pathways.
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PMID:Expression of nitric oxide synthase in skeletal muscle: a novel role for nitric oxide as a modulator of insulin action. 935 14

The distributions of nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) and nitric oxide synthase (NOS) in mammalian cochlea were studied at light and electron microscope levels by NADPH-d histochemistry and brain NOS (bNOS) immunohistochemistry. The cochleae from 15 albino guinea pigs were perilymphatically fixed with 2% periodate-lysine-paraformaldehyde, decalcified in 10% EDTA and processed for light and electron microscopy after NADPH-d or NOS staining in frozen and vibratome sections respectively. One human cochlea was available for light microscope examination of NADPH-d or bNOS stained sections. Light microscope results revealed that type I neurons and nerve fibers of the spiral ganglion cells were labeled by bNOS immunohistochemistry as well as NADPH-d histochemistry in both guinea pig and human cochleae. At subcellular level, NADPH-d reaction product was localized in the mitochondria of the neuronal cytoplasm and axoplasm and in the cytoplasm of the vascular endothelium. The immunoreaction products of bNOS were evenly distributed in the neuronal cytoplasm and axoplasm. Myelinated and unmyelinated fibers in the intraganglionic spiral bundle and the inner spiral and inner radial fibers below the inner hair cells were labeled for bNOS. The nerve endings below the outer hair cells were not stained. NOS immunoreaction product was also found in the outer hair cells, Schwann cells of myelinated nerve fibers, Deiter's cells, pillar cells and the tympanic lamina cells. No difference was found in the staining pattern of both NADPH-d and NOS reaction products between human and guinea pig cochleae at the light microscope level. The results suggest that NO plays an important role in the maintenance of auditory function in the mammal.
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PMID:Localization of nitric oxide synthase and NADPH-diaphorase in guinea pig and human cochleae. 947 7

NAD(P)H:quinone oxidoreductase (NQO1) is a flavoenzyme that catalyzes the two-electron reduction of quinones and related compounds. With the use of biochemical assays, NQO1 has been shown to be overexpressed in many types of cancer, including non-small cell lung cancer (NSCLC). NQO1 can bioactivate antitumor quinones such as mitomycin C, and new quinone-based drugs are currently being developed to target this enzyme in tumors such as NSCLC. Because there is no information on the cell-specific expression of NQO1 in lung, the purpose of this study was to examine the expression of NQO1 in human NSCLC, small cell lung cancer, carcinoid lung tumors, and normal lung using immunohistochemistry. A high level of NQO1 protein expression was detected by immunohistochemistry in NSCLC (adenocarcinoma, squamous cell carcinoma, and bronchoalveolar carcinoma), but no NQO1 protein could be detected in small cell lung cancer or carcinoid lung tumors. In addition, NQO1 protein expression was examined by immunohistochemistry in normal lung tissue. A high level of NQO1 protein expression was detected by immunohistochemistry in normal lung respiratory epithelium, with the highest levels of expression observed in ciliated columnar epithelial cells. Significant amounts of NQO1 protein were also detected in the vascular endothelium and adipocytes. These data demonstrate that NQO1 is overexpressed in NSCLC. Cells in normal lung also contain marked NQO1 protein and may be damaged by drugs activated by NQO1. These data validate NSCLC as a target for NQO1-directed agents and suggest that the potential for lung toxicity be considered in the preclinical development of quinone-based antitumor drugs.
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PMID:Immunohistochemical detection of NAD(P)H:quinone oxidoreductase in human lung and lung tumors. 974 20

Nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry was used to demonstrate the presence of nitric oxide in the developing chicken thymus. NADPH-d was first expressed in the epithelial cells located at the corticomedullary junction of the thymic rudiment on day 13 of incubation. The number of labelled cells gradually increased from day 13 to day 21. Ultrastructural evidence showed that the labelling was localized in a heterogeneous population of cells in the medulla near the corticomedullary junction, comprising the cystic, undifferentiated, myoid, lymphoid and epithelial reticular cells. At this age, the vascular endothelium was NADPH-d positive. Labelling was also detected in some macrophages. The reaction product primarily labelled profiles of rough endoplasmic reticulum and to a lesser extent the outer membranes of mitochondria, portions of the nuclear envelope and the Golgi apparatus. By day 18/19, NADPH-d-labelled nerve fibres were occasionally observed in the interlobular connective tissue. By day 21, these fibres formed perivascular plexuses. Labelled nerve fibres were occasionally observed in the medullary parenchyma. Possible functions of nitric oxide in the embryonic thymus are discussed.
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PMID:Ontogeny of NADPH-d expression in the thymic microenvironment of the chick embryo. 979 49

The NAD(P)H:quinone oxidoreductase 1 (NQO1) genotype-phenotype relationship was examined in individuals with a polymorphism in NQO1. The polymorphism comprises a C to T base change at position 609 of the human NQO1 cDNA (C609T) and codes for a proline to serine substitution in the amino acid structure of the NQO1 protein. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism analysis of genomic DNA. Phenotyping was performed using enzyme activity assays and/or immunoblotting of human tumor cell lines and of saliva and bone marrow samples from healthy donors. Phenotyping of uninvolved lung and lung tumors from archived biopsy material was performed by immunohistochemistry. NQO1 activity and protein could be detected in wild-type (C/C) human tumor cells (HT-29) under conditions where NQO1 protein could not be detected in cells (BE) homozygous for the C609T change (T/T). Trace levels of NQO1 protein could be detected in BE cells; however, when immunoblots were subjected to chemiluminescence detection for prolonged periods. In saliva samples from 11 individuals carrying the homozygous C609T change (T/T), no NQO1 protein could be detected even after prolonged chemiluminescence detection. The amount of NQO1 protein present in saliva was quantified and found to be significantly less in heterozygous individuals (C/T) than in wild-type individuals (C/C). In bone marrow stromal cultures, both NQO1 activity and protein could be detected in heterozygotes (C/T) and in wild-type (C/C) samples. In a bone marrow stromal culture from an individual genotyped as T/T at position 609, no NQO1 protein or activity could be detected. NQO1 is elevated in non-small cell lung cancers and could be readily observed as intense immunostaining throughout lung adenocarcinomas genotyped as C/C but no immunostaining could be detected in adenocarcinomas genotyped as T/T at position 609. NQO1 is expressed in normal human lung but is localized to respiratory epithelium and to vascular endothelium. In normal lung tissue from individuals genotyped as T/T, no or faint immunostaining for NQO1 could be detected in either respiratory epithelium or vascular endothelium. These results demonstrate that tissues from individuals homozygous for the C609T change have no detectable or, at best, only trace amounts of NQO1 protein and are devoid of NQO1 activity.
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PMID:Genotype-phenotype relationships in studies of a polymorphism in NAD(P)H:quinone oxidoreductase 1. 1020 50

Experiments were carried out to investigate the functional and anatomical relationships between neuronal elements and cerebral microvessels in 300-350-microm thick coronal hippocampal slices maintained at 33-35 degrees C, obtained from 150-200 g male Wistar rats. Cerebral arterioles (9-22 microm in diameter) were visualized in situ and pre-constricted by 22.0+/-6.6% by the addition of the thromboxane A2 agonist U46619 (75 nM), to the bathing medium. The glutamate agonist N-methyl-D-aspartate (0.01-1 mM) produced a dose-related increase in luminal diameter of pre-constricted vessels. In the presence of 4 microM haemoglobin to scavenge nitric oxide from the extravascular environment of the slice, the increase in diameter evoked by 0.1 mM N-methyl-D-aspartate was significantly reduced from 17.5+/-4.6% to 4.8+/-1.7% indicating that N-methyl-D-aspartate-induced vasodilatation of cerebral microvessels is mediated via a mechanism which involves neuronally-derived nitric oxide. In a parallel anatomical study, beta-nicotinamide adenine dinucleotide phosphate-dependent diaphorase staining was used to reveal the enzyme nitric oxide synthase in vascular endothelium and neurons in slices. A small subpopulation (< 11 cells per slice) of darkly-stained multipolar neurons, 21-32 microm in diameter was observed to give rise to a dense network of fine diaphorase-reactive nerve fibres that ramified throughout the whole of the hippocampus and appeared to come into close apposition with arterioles. Morphometric analysis of the relationship between cerebral microvessels, beta-nicotinamide adenine dinucleotide phosphate, reduced form-dependent diaphorase-reactive neuronal elements and individual pyramidal layer neurons, identified by filling with biocytin, revealed that for a given point on a pyramidal layer neuron, the proximity of the nearest diaphorase-reactive nerve fibre was less than 10 microm, whilst the distance to the nearest arteriole (the smallest functional unit for controlling blood flow) was in excess of 70 microm. Such a distance would probably preclude diffusion of vasoactive metabolites in effective concentrations from the area of increased neuronal activity. We therefore propose that the diaphorase-reactive nerve network constitutes the functional link. It is possible that during periods of increased neuronal activity, spillover of glutamate from synapses may activate the diaphorase-reactive network. Release of nitric oxide from the network in the vicinity of local cerebral arterioles may then produce relaxation of the vascular smooth muscle, enabling increased blood flow into the capillary network supplying the region of increased metabolic activity. This study has shown that the process whereby increases in neuronal activity elicit a local change in cerebral blood flow remains functionally intact in hippocampal slice preparations. Nitric oxide of neuronal origin appears to be involved in mediating the coupling between neurons and cerebral arterioles. Stereological analysis of the relationship between neuronal and vascular elements within hippocampal slices suggested that a small subpopulation of nitric oxide synthase-containing neurons which give rise to a diffuse network of fine nitric oxide synthase-containing nerve fibres that lie in close apposition to cerebral arterioles may provide the anatomical substrate for coupling of blood flow to metabolism.
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PMID:Neurovascular relationships in hippocampal slices: physiological and anatomical studies of mechanisms underlying flow-metabolism coupling in intraparenchymal microvessels. 1039 29

Despite the extensive interest in NADPH:quinone oxidoreductase (NQO1, DT-diaphorase), there is little immunohistochemical information regarding its distribution in either normal human tissues or in human tumors. Using immunohistochemistry (IHC), we have examined cell-specific expression of NQO1 in many normal tissues and tumors as a step toward defining the distribution of NQO1 in humans. NQO1 was detected by IHC in respiratory, breast duct, thyroid follicle, and colonic epithelium, as well as in the corneal and lens epithelium of the eye. NQO1 was also detected by IHC in vascular endothelium in all tissues examined. NQO1 could also readily be detected in the endothelial lining of the aorta but was not detected using immunoblot analysis in the myocardium. Adipocytes stained positive for NQO1, and the enzyme was also detected by both IHC and immunoblot analysis in parasympathetic ganglia in the small intestine and in the optic nerve and nerve fibers. NQO1 was not highly expressed in five different human liver samples using immunoblot analysis, whereas studies using IHC demonstrated only trace NQO1 staining in isolated bile duct epithelium. NQO1 expresion was also examined by IHC in a variety of solid tumors. Marked NQO1 staining was detected in solid tumors from thyroid, adrenal, breast, ovarian, colon, and cornea and in non-small cell lung cancers. The NQO1 content of many solid tumors supports the use of NQO1-directed anticancer agents for therapeutic purposes, but the distribution of NQO1 in normal tissues suggests that potential adverse effects of such agents need to be carefully monitored in preclinical studies.
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PMID:Immunodetection of NAD(P)H:quinone oxidoreductase 1 (NQO1) in human tissues. 1103 53

Nitric oxide (NO) is a novel gaseous intercellular transmitter thought to play important physiological roles in the regulation of blood flow and hormone secretion in, for example, the pituitary, the thyroid, and the endocrine pancreas. Whether nitric oxide synthase (NOS) is present in the human parathyroid glands has not yet been demonstrated. In the present study, histologically normal, but functionally suppressed human parathyroid glands and parathyroid adenomas from patients with primary hyperparathyroidism were investigated by immunocytochemistry with antibodies against neuronal NOS and by reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry. We also used H&E to identify the NOS-immunoreactive cells. Immunocytochemistry demonstrated the presence of neuronal-type NOS in a subpopulation of glandular cells, identified as oxyphilic cells, in both normal parathyroid glands and adenomas. NADPH-diaphorase staining visualized NOS in the endothelium of blood vessels and in glandular cells, corresponding to those containing immunoreactive NOS. In addition, we found NADPIH-diaphorase staining in many chief cells. Our results indicate that both glandular cells and vascular endothelium in human parathyroid glands and adenomas express NOS. There is thus a morphological substrate for locally produced NO that may be involved in the regulation of parathyroid blood flow and hormone secretion.
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PMID:Nitric Oxide Synthase in Human Parathyroid Glands and Parathyroid Adenomas. 1211 33

Ischemic preconditioning (IPC) may protect the liver from ischemia reperfusion injury by nitric oxide formation. This study has investigated the effect of ischemic preconditioning on hepatic microcirculation (HM), and the relationship between nitric oxide metabolism and HM in preconditioning. Rats were allocated to 5 groups: 1. sham laparotomy; 2. 45 minutes lobar ischemia followed by 2-hour reperfusion (IR); 3. IPC with 5 minutes ischemia and 10 minutes reperfusion before IR; 4. L-arginine before IR; and 5. L-NAME + IPC before IR. HM was monitored by laser Doppler flowmeter. Liver transaminases, adenosine triphosphate, nitrites + nitrates, and guanosine 3'5'-cyclic monophosphate (cGMP) were measured. Nitric oxide synthase (NOS) distribution was studied using nicotinamide adeninine dinucleotide phosphate (NADPH) diaphorase histochemistry. At the end of reperfusion phase, in the IR group, flow in the HM recovered partially to 25.8% of baseline (P < .05 versus sham), whereas IPC improved HM to 49.5% of baseline (P < .01 versus IR). With L-arginine treatment, HM was 31.6% of baseline (NS versus IR), showing no attenuation of liver injury. In the preconditioned group treated with L-NAME, HM declined to 10.2% of baseline, suggesting not only a blockade of the preconditioning effect, but also an exacerbated liver injury. Hepatocellular injury was reduced by IPC, and L-arginine and was increased by NO inhibition with L-NAME. IPC also increased nitrate + nitrate (NOx) and cGMP concentrations. NOS detected by NADPH diaphorase staining was associated with hepatocytes and vascular endothelium, and was induced by IPC. IPC induced NOS and attenuated HM impairment and hepatocellular injury. These data strongly suggest a role for nitric oxide in IPC.
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PMID:Effect of ischemic preconditioning on hepatic microcirculation and function in a rat model of ischemia reperfusion injury. 1247 59

We investigated co-adaptation of enzymatic systems of cells using data on activity of NAD(Ph)-dependent enzymes and AgNOR proteins of vascular endothelium vis-a-vis angiogenesis in benign and malignant smooth muscle tumors of the corpus uteri. Overall metabolic activity (NAD-H2 diaphorase) was found to directly correlate with angiogenesis and endothelial vessel proliferation (r = 0.76 and 0.84, respectively). SDH-regulated oxidation in the main metabolic succession of a tricarbonic acid cycle depended on blood supply and endothelial vessel proliferation (r = 0.84 and 0.92, respectively; p = 0.04). A similar relationship was shown for anaerobic glycolysis of SDH (LDH content), on the one hand, and blood supply and endothelial vessel proliferation(r = 0.57 and 0.70, respectively; p = 0.02), on the other. Hence, metabolic profile varied in unaltered myometrium and tumor with variable cellular density and peculiar extracellular matrix. The highest levels of metabolic activity with NAD(Ph)-dependent enzyme co-adaptation was observed in sarcomas which were also characterized by the highest vascular density for endothelial proliferation.
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PMID:[Co-adaptation of enzymatic systems of cells and blood supply in smooth muscle tumors of the corpus uteri]. 1906 75


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