Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.99.1 (NADPH-diaphorase)
 3,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The amount of messenger RNA encoding human inducible nitric oxide synthase and the presence and distribution of NADPH diaphorase were determined in tissue sections from multiple sclerosis (MS) and control brains. Levels of human nitric oxide synthase messenger RNA were markedly elevated in MS brains when compared to normal control brains. NADPH diaphorase activity, a histochemical stain reflecting nitric oxide synthase catalytic activity, was detected in reactive astrocytes in active demyelinating MS lesions and at the edge of chronic active demyelinating lesions. Control brains did not contain NADPH diaphorase-positive astrocytes. These results implicate the free radical nitric oxide in the pathogenesis of demyelinating MS lesions.
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PMID:Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. 752 76

Nitric oxide (NO) is a recently recognized messenger molecule that has been shown to possess pleiotropic properties, including vasodilation, neurotransmission, cytotoxicity and antimicrobial activity. Constitutive and inducible forms of NO synthase (NOS) have been identified. Activation of cNOS releases relatively low levels of NO for short periods of time whereas induction of iNOS releases high levels of NO for extended periods of time. In rodents, iNOS is predominantly found in cells of the monocyte/macrophage series, including microglia, where it is induced by a combination of bacterial products and cytokines. cNOS and iNOS have also been reported in rodent astrocytes. Activation of iNOS in the CNS could be toxic to many different cell types, including neurons and oligodendrocytes. iNOS, however, has been difficult to demonstrate in human peripheral blood cells, suggesting that the regulation of expression of this enzyme in humans is different from that found in rodents. In this overview, we show that in human glial cells cultured in vitro, astrocytes, but not microglia, can be induced by cytokines to express NO-like activity. Bacterial products are without effect, but a combination of IL-1 and TNF alpha or IFN gamma is a potent stimulus. NO production by astrocytes inhibits Cryptococcus neoformans growth in vitro. In vivo, we show in acute multiple sclerosis lesions, intense NADPH-diaphorase activity is present in hypertrophic astrocytes in the lesion center and at the lesion edge, whereas microglia are nonreactive. Increased NADPH-diaphorase activity colocalizes with immunoreactivity for IL-1 and TNF. These results suggests that the induction of reactive nitrogen intermediates in humans differs from that found in rodents, and supports the conclusion that hypertrophic astrocytes are the major source of NO-like activity in the inflamed CNS.
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PMID:Reactive nitrogen intermediates in human neuropathology: an overview. 753 80

The cellular localization and distribution of inducible and constitutive nitric oxide synthase (iNOS/cNOS) was determined in tissue sections from multiple sclerosis (MS) and control brain and spinal cord. Immunocytochemical techniques were applied using specific iNOS- and cNOS-directed antibodies. In addition, NADPH-diaphorase histochemistry was performed. To establish the identity of iNOS-, cNOS- and NADPH-diaphorase-positive cells single and double staining was performed on tissue sections with the macrophage marker KP1 (CD68) and with the astrocyte marker glial fibrillary acidic protein (GFAP). Areas of myelin breakdown and demyelination were determined using a staining for neutral lipids, Oil Red O (ORO). Furthermore, macrophages isolated from active demyelinating MS lesions were stained for iNOS, cNOS, KP1 and ORO. In active MS lesions strong iNOS immunoreactivity was found exclusively in perivascular and parenchymal macrophages distributed within regions of active demyelination. In these active MS lesions immunoreactivity for cNOS was also found in macrophages. Macrophages isolated from active MS lesions also showed immunoreactivity for iNOS and cNOS. Moreover, these isolated macrophages produced nitric oxide (NO; >30 microM) in vitro. NADPH-diaphorase activity was detected in KP1-positive perivascular and parenchymal macrophages and in GFAP-positive reactive astrocytes in active MS lesions and in reactive astrocytes located in the hypercellular rims of chronic active MS lesions. cNOS-positive reactive astrocytes were detected in both active and chronic active MS lesions. Inside chronic active lesions some residual macrophages were weakly iNOS-positive. In control brain and spinal cord no iNOS immunoreactivity could be detected. These results suggests an important role for human macrophages capable of producing the free radical nitric oxide (NO), which may contribute to the cytotoxicity of oligodendrocytes and destruction of myelin in MS brain and spinal cord.
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PMID:Immunocytochemical characterization of the expression of inducible and constitutive isoforms of nitric oxide synthase in demyelinating multiple sclerosis lesions. 899 Jan 25

We recently identified the inducible isoform of nitric oxide synthase (iNOS) in inflammatory lesions of the central nervous system (CNS) in mice with experimental allergic encephalomyelitis (EAE), a known animal model of multiple sclerosis (MS). In the present study, the role of excessive nitric oxide (NO) production via iNOS was investigated in mice with EAE using immunohistochemistry with antibodies to nitrotyrosine and iNOS, NADPH-diaphorase histochemistry, and the in situ terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) method to detect cell death, presumably through an apoptotic mechanism. NADPH-diaphorase histochemistry and immunohistochemistry for iNOS revealed an elevation of nitric oxide synthase (NOS) activity during the course of EAE, which came from iNOS. Nitrotyrosine was detected in infiltrated cells and some glial cells in the spinal cord lesions, where iNOS-positive inflammatory cells were present at the peak of EAE. The findings implied the generation of NO and peroxynitrite in the EAE lesions, which might damage structural and functional proteins. The TUNEL positive cells were mainly inflammatory ones, and most of them were located in close proximity to iNOS-positive cells, while some of them were iNOS-positive themselves. These results suggested that excessive NO via iNOS played an important role to eliminate inflammatory cells in the CNS of mice with EAE, possibly through an apoptotic mechanism.
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PMID:Nitric oxide via an inducible isoform of nitric oxide synthase is a possible factor to eliminate inflammatory cells from the central nervous system of mice with experimental allergic encephalomyelitis. 905 66