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
Query: EC:1.6.3.1 (
NADPH oxidase
)
11,281
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The results of past research studies show that platelets are one of the main sources of reactive oxygen species (ROS) and reactive nitrogen species (RNS) to be found in the course of many pathological states. The aim of this study was to determine the level of oxidative/nitrative stress biomarkers in blood platelets obtained from
multiple sclerosis
(MS) patients (
n
= 110) and to verify their correlation with the clinical parameters of the psychophysical disability of patients. The mitochondrial metabolism of platelets was assessed by measuring the intracellular production of ROS using the fluorescence method with DCFH-DA dye and by identification of changes in the mitochondrial membrane potential of platelets using the JC-1 dye. Moreover, we measured the mRNA expression for the gene encoding the cytochrome c oxidase subunit I (
MTCO-1
) and glyceraldehyde 3-phosphate dehydrogenase (
GAPDH
) in platelets and megakaryocytes using the RT-qPCR method, as well as the concentration of
NADPH oxidase
(NOX-1) by the ELISA method. Our results proved an increased level of oxidative/nitrative damage of proteins (carbonyl groups, 3-nitrotyrosine) (
p
< 0.0001) and decreased level of -SH in MS (
p
< 0.0001) and also a pronounced correlation between these biomarkers and parameters assessed by the Expanded Disability Status Scale and the Beck's Depression Inventory. The application of fluorescence methods showed mitochondrial membrane potential disruption (
p
< 0.001) and higher production of ROS in platelets from MS compared to control (
p
< 0.0001). Our research has also confirmed the impairment of red-ox metabolism in MS, which was achieved by increasing the relative mRNA expression in platelets for the genes studied (2-fold increase for the
MTCO-1
gene and 1.5-fold increase in
GAPDH
gene,
p
< 0.05), as well as the augmented concentration of NOX-1 compared to control (
p
< 0.0001). Our results indicate that the oxidative/nitrative damage of platelets is implicated in the pathophysiology of MS, which reflects the status of the disease.
...
PMID:Oxidative Damage of Blood Platelets Correlates with the Degree of Psychophysical Disability in Secondary Progressive Multiple Sclerosis. 3265 63
Age is a critical risk factor for many neurologic conditions, including progressive
multiple sclerosis
. Yet the mechanisms underlying the relationship are unknown. Using lysolecithin-induced demyelinating injury to the mouse spinal cord, we characterized the acute lesion and investigated the mechanisms of increased myelin and axon damage with age. We report exacerbated myelin and axon loss in middle-aged (8-10 months of age) compared with young (6 weeks of age) female C57BL/6 mice by 1-3 d of lesion evolution in the white matter. Transcriptomic analysis linked elevated injury to increased expression of
Cybb
, the gene encoding the catalytic subunit of
NADPH oxidase
gp91phox. Immunohistochemistry in male and female
Cx
3
cr1
CreER
/+
:Rosa26
tdTom
/+
mice for gp91phox revealed that the upregulation in middle-aged animals occurred primarily in microglia and not infiltrated monocyte-derived macrophages. Activated
NADPH oxidase
generates reactive oxygen species and elevated oxidative damage was corroborated by higher malondialdehyde immunoreactivity in lesions from middle-aged compared with young mice. From a previously conducted screen for generic drugs with antioxidant properties, we selected the antihypertensive CNS-penetrant medication indapamide for investigation. We report that indapamide reduced superoxide derived from microglia cultures and that treatment of middle-aged mice with indapamide was associated with a decrease in age-exacerbated lipid peroxidation, demyelination and axon loss. In summary, age-exacerbated acute injury following lysolecithin administration is mediated in part by microglia
NADPH oxidase
activation, and this is alleviated by the CNS-penetrant antioxidant, indapamide.
SIGNIFICANCE STATEMENT
Age is associated with an increased risk for the development of several neurologic conditions including progressive
multiple sclerosis
, which is represented by substantial microglia activation. We demonstrate that in the lysolecithin demyelination model in young and middle-aged mice, the latter group developed greater acute axonal and myelin loss attributed to elevated oxidative stress through
NADPH oxidase
in lineage-traced microglia. We thus used a CNS-penetrant generic medication used in hypertension, indapamide, as we found it to have antioxidant properties in a previous drug screen. Following lysolecithin demyelination in middle-aged mice, indapamide treatment was associated with decreased oxidative stress and axon/myelin loss. We propose indapamide as a potential adjunctive therapy in aging-associated neurodegenerative conditions such as Alzheimer's disease and progressive
multiple sclerosis
.
...
PMID:Aging-Exacerbated Acute Axon and Myelin Injury Is Associated with Microglia-Derived Reactive Oxygen Species and Is Alleviated by the Generic Medication Indapamide. 3306 Jan 75
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