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: UNIPROT:P47989 (xanthine oxidase)
8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Astrocytes, the most abundant glial cell types in the brain, provide metabolic and trophic support to neurons and modulate synaptic activity. Accordingly, impairment in these astrocyte functions can critically influence neuronal survival. Recent studies show that astrocyte apoptosis may contribute to pathogenesis of many acute and chronic neurodegenerative disorders, such as cerebral ischemia, Alzheimer's disease and Parkinson's disease. We found that incubation of cultured rat astrocytes in a Ca(2+)-containing medium after exposure to a Ca(2+)-free medium causes an increase in intracellular Ca(2+) concentration followed by apoptosis, and that NF-kappa B, reactive oxygen species, and enzymes such as calpain, xanthine oxidase, calcineurin and caspase-3 are involved in reperfusion-induced apoptosis. Furthermore, we demonstrated that heat shock protein, mitogen-activated protein/extracellular signal-regulated kinase, phosphatidylinositol-3 kinase and cyclic GMP phosphodiesterase are target molecules for anti-apoptotic drugs. This review summarizes (1) astrocytic functions in neuroprotection, (2) current evidence of astrocyte apoptosis in both in vitro and in vivo studies including its molecular pathways such as Ca(2+) overload, oxidative stress, NF-kappa B activation, mitochondrial dysfunction, endoplasmic reticulum stress, and protease activation, and (3) several drugs preventing astrocyte apoptosis. As a whole, this article provides new insights into the potential role of astrocytes as targets for neuroprotection. In addition, the advance in the knowledge of molecular mechanisms of astrocyte apoptosis may lead to the development of novel therapeutic strategies for neurodegenerative disorders.
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PMID:Astrocyte apoptosis: implications for neuroprotection. 1506 28

Amyloid precursor protein (AbetaPP), a precursor of amyloid beta (Abeta) peptide, is one of the molecules involved in the pathogenesis of Alzheimer's disease (AD). Specific mutations in AbetaPP have been found in patients inheriting familial AD (FAD). These mutant AbetaPP proteins cause cell death in neuronal cell lines in vitro, but the molecular mechanism of cytotoxicity has not yet been clarified completely. We analyzed the cytotoxic mechanisms of the London-type AbetaPP mutant, V642I-AbetaPP, in primary cortical neurons utilizing an adenovirus-mediated gene transfer system. Expression of V642I-AbetaPP protein induced degeneration of the primary neurons. This cytotoxicity was blocked by pertussis toxin, a specific inhibitor for heterotrimeric G proteins, Go/i, and was suppressed by an inhibitor of caspase-3/7 and an antioxidant, glutathione ethyl ester. A specific inhibitor for NADPH oxidase, apocynin, but not a xanthine oxidase inhibitor or a nitric oxide inhibitor, blocked V642I-AbetaPP-induced cytotoxicity. Among mitogen-activated protein kinase (MAPK) family proteins, c-Jun N-terminal kinase (JNK) and p38MAPK, but not extracellular regulated kinase (ERK), were involved in this cytotoxic pathway. The V642I-AbetaPP-induced cytotoxicity was not suppressed by two secretase inhibitors, suggesting that Abeta does not play a major role in this cytotoxicity. Two neuroprotective factors, insulin-like growth factor I (IGF-I) and Humanin, protected these primary neurons from V642I-AbetaPP-induced cytotoxicity. Furthermore, interleukin-6 and -11 also attenuated this cytotoxicity. This study demonstrated that the signaling pathway activated by mutated AbetaPP in the primary neurons is the same as that by the other artificial insults such as antibody binding to AbetaPP and the artificial dimerization of cytoplasmic domain of AbetaPP. The potential of neurotrophic factors and cytokines in AD therapy is also indicated.
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PMID:Characterization of V642I-AbetaPP-induced cytotoxicity in primary neurons. 1519 38

Although neurotoxic functions are well characterized in familial Alzheimer's disease (FAD)-linked N141I mutant of presenilin (PS)2, little has been known about M239V-PS2, another established FAD-causative mutant. We found that expression of M239V-PS2 caused neuronal cytotoxicity. M239V-PS2 exerted three forms of cytotoxicity: one was sensitive to both an antioxidant glutathione-ethyl-ester (GEE) and a caspase inhibitor Ac-DEVD-CHO (DEVD); the second was sensitive to GEE but resistant to DEVD; and the third was resistant to both. The GEE/DEVD-sensitive cytotoxicity by M239V-PS2 was likely through NADPH oxidase and the GEE-sensitive/DEVD-resistant cytotoxicity through xanthine oxidase (XO). Both mechanisms by M239V-PS2 were suppressed by pertussis toxin (PTX) and were mediated by Galpha(o), but not by Galpha(i). Although Abeta1-43 itself induced no cytotoxicity, Abeta1-43 potentiated all three components of M239V-PS2 cytotoxicity. As these cytotoxic mechanisms by M239V-PS2 are fully shared with N141I-PS2, they are most likely implicated in the pathomechanism of FAD by PS2 mutations. Notably, cytotoxicity by M239V-PS2 could be inhibited by the combination of two clinically usable inhibitors of superoxide-generating enzymes, apocynin and oxypurinol.
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PMID:Cytotoxic mechanisms by M239V presenilin 2, a little-analyzed Alzheimer's disease-causative mutant. 1526 28

Alzheimer's disease is a major illness of dementia characterized by the presence of amyloid plaques, neurofibrillary tangles, and extensive neuronal apoptosis. However, the mechanism behind neuronal apoptosis in the Alzheimer's-diseased brain is poorly understood. This study underlines the importance of neutral sphingomyelinase in fibrillar Abeta peptide-induced apoptosis and cell death in human primary neurons. Abeta1-42 peptides induced the activation of sphingomyelinases and the production of ceramide in neurons. Interestingly, neutral (N-SMase), but not acidic (A-SMase), sphingomyelinase was involved in Abeta1-42-mediated neuronal apoptosis and cell death. Abeta1-42-induced production of ceramide was redox-sensitive, as reactive oxygen species were involved in the activation of N-SMase but not A-SMase. Abeta1-42 peptides induced the NADPH oxidase-mediated production of superoxide radicals in neurons that was involved in the activation of N-SMase, but not A-SMase, via hydrogen peroxide. Consistently, superoxide radicals generated by hypoxanthine and xanthine oxidase also induced the activation of N-SMase, but not A-SMase, through a catalase-sensitive pathway. Furthermore, antisense knockdown of p22phox, a subunit of NADPH oxidase, inhibited Abeta1-42-induced neuronal apoptosis and cell death. These studies suggest that fibrillar Abeta1-42 peptides induce neuronal apoptosis through the NADPH oxidase-superoxide-hydrogen peroxide-NS-Mase-ceramide pathway.
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PMID:Fibrillar amyloid-beta peptides kill human primary neurons via NADPH oxidase-mediated activation of neutral sphingomyelinase. Implications for Alzheimer's disease. 1545 32

The incidence of Alzheimer disease is increased following ischemic episodes, and we previously demonstrated that following chronic hypoxia (CH), amyloid beta (Abeta) peptide-mediated increases in voltage-gated L-type Ca(2+) channel activity contribute to the Ca(2+) dyshomeostasis seen in Alzheimer disease. Because in certain cell types mitochondria are responsible for detecting altered O(2) levels we examined the role of mitochondrial oxidant production in the regulation of recombinant Ca(2+) channel alpha(1C) subunits during CH and exposure to Abeta-(1-40). In wild-type (rho(+)) HEK 293 cells expressing recombinant L-type alpha(1C) subunits, Ca(2+) currents were enhanced by prolonged (24 h) exposure to either CH (6% O(2)) or Abeta-(1-40) (50 nm). By contrast the response to CH was absent in rho(0) cells in which the mitochondrial electron transport chain (ETC) was depleted following long term treatment with ethidium bromide or in rho(+) cells cultured in the presence of 1 microm rotenone. CH was mimicked in rho(0) cells by the exogenous production of O2(-.). by xanthine/xanthine oxidase. Furthermore Abeta-(1-40) enhanced currents in rho(0) cells to a degree similar to that seen in cells with an intact ETC. The antioxidants ascorbate (200 microm) and Trolox (500 microm) ablated the effect of CH in rho(+) cells but were without effect on Abeta-(1-40)-mediated augmentation of Ca(2+) current in rho(0) cells. Thus oxidant production in the mitochondrial ETC is a critical factor, acting upstream of amyloid beta peptide production in the up-regulation of Ca(2+) channels in response to CH.
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PMID:Hypoxic augmentation of Ca2+ channel currents requires a functional electron transport chain. 1582 10

For the last 15 yr, a great deal of knowledge has been accumulated on health beneficial factors, protein and nonprotein, of bovine milk fat globule membrane (MFGM). Among the health-beneficial components of the MFGM are cholesterolemia-lowering factor, inhibitors of cancer cell growth, vitamin binders, inhibitor of Helicobacter pylori, inhibitor of beta-glucuronidase of the intestinal Escherichia coli, xanthine oxidase as a bactericidal agent, butyrophilin as a possible suppressor of multiple sclerosis, and phospholipids as agents against colon cancer, gastrointestinal pathogens, Alzheimer's disease, depression, and stress. All of the above compel us to consider bovine MFGM as a potential nutraceutical.
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PMID:Invited review: Bovine milk fat globule membrane as a potential nutraceutical. 1595 91

Abnormalities in calcium homeostasis and oxidative processes occur in fibroblasts from patients with Alzheimer disease (AD) and in fibroblasts and neurons from transgenic mice bearing a presenilin-1 (PS-1) mutation. Bombesin-releasable endoplasmic reticulum Ca2+ stores (BRCS) are exaggerated in all of these cells. Our previous studies show that H2O2 exaggerates BRCS. The goal of the present study was to determine whether select reactive species exaggerate BRCS in cultured human fibroblasts and to determine if the ability of fibroblasts to handle these specific oxidant species is altered in cells from AD patients. Two fluorescent indicators were used to distinguish different reactive oxygen species (ROS): 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate, di(acetoxymethyl ester) (c-DCF) and 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM). ROS were produced by a variety of oxidants, including tert-butyl-hydroxyperoxide (t-BHP), hypoxanthine/xanthine oxidase, S-nitroso-N-acetylpenicillamine, 3-morpholinosydnonimine, and sodium nitroprusside. Different oxidants selectively induced various ROS in distinct patterns. These oxidants also induced selective modification in [Ca2+]i and/or BRCS. Of the several oxidants tested, t-BHP was most specific for exaggerating BRCS without affecting basal [Ca2+]i and inducing only c-DCF-detectable ROS. On the other hand, the results show that NO that reacted with DAF-FM was not responsible for alterations in BRCS. Furthermore, the c-DCF-detectable ROS production induced by t-BHP was higher in fibroblasts from AD patients bearing a PS-1 mutation (n = 7) than in those from aged controls (n = 8). The higher production of c-DCF-detectable ROS may underlie the exaggeration of BRCS in fibroblasts from AD patients. Thus, these results are consistent with the hypothesis that abnormalities in selective cellular ROS cause AD-related changes in intracellular calcium regulation.
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PMID:Modification of endoplasmic reticulum Ca2+ stores by select oxidants produces changes reminiscent of those in cells from patients with Alzheimer disease. 1619 25

Mounting evidence has shown that dyshomeostasis of the redox-active biometals such as Cu and Fe can lead to oxidative stress, which plays a key role in the neuropathology of Alzheimer' disease (AD). Here we demonstrate that with the formation of Cu(II).beta1-40 complexes, copper markedly potentiates the neurotoxicity exhibited by beta-amyloid peptide (Ab). A greater amount of hydrogen peroxide was released when Cu(II).beta1-40 complexes was added to the xanthine oxidase/xanthine system detected by potassium iodide spectrophotometry. Copper bound to Abeta1-40 was observed by electron paramagnetic resonance (EPR) spectroscopy. Circular dichroism (CD) studies indicated that copper chelation could cause a structural transition of Abeta. The addition of copper to Ab introduced an increase on beta-sheet as well as alpha-helix, which may be responsible for the aggregation of Abeta. We hypothesized that Abeta aggregation induced by copper may be responsible for local injury in AD. The interaction between Cu(2+) and Ab also provides a possible mechanism for the enrichment of metal ions in amyloid plaques in the AD brain.
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PMID:Cu(II) potentiation of Alzheimer Abeta1-40 cytotoxicity and transition on its secondary structure. 1709 Nov 93

Peroxynitrite (ONOO-) is a reactive nitrogen specie produced by the reaction between nitric oxide (NO*) and superoxide anion (O2*-). NO* is produced by nitric oxide synthase (NOS) and O2*- is formed by the addition of an electron to O2 in enzymatic as well as nonenzymatic way. NADPH oxidase and xanthine oxidase are some of the enzymes involved in O2*- formation. ONOO- is an oxidant specie which is able to modify a great number of biomolecules such as aminoacids, proteins, enzymes and cofactors. ONOO- is able to induce nitration leading to the formation of 3-nytrotyrosine. This change has been widely studied, and although it is not only produced by ONOO-, but also by other reactive nitrogen species, it has been accepted like footprint of ONOO-. The excessive production of reactive nitrogen species is known as nitrosative stress that is able to induce structural damage leading to the loss of cell function. Furthermore, synthetic metalloporphyrins that metabolize ONOO- in a specific way are being used to determine if ONOO- is involved in different diseases, such as Alzheimer, Huntington, diabetes, hypertension, arthritis, colitis, cardiac and renal complications. Finally, these metalloporphyrins may be of potential therapeutic value in diseases related to ONOO- production.
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PMID:[Role of peroxynitrite anion in different diseases]. 1714 46

The free radical-generating system of xanthine and xanthine oxidase is commonly used experimentally as a source of superoxide anion, which can produce oxidative stress, leading to cellular damage and death. Models of oxidative stress are important in elucidating pathologies associated with increased levels of reactive oxygen species, including stroke and neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. We therefore, examined the effect of the xanthine/xanthine oxidase system on the viability of postnatal cerebellar granule neurones obtained from 8-day old Sprague-Dawley rat pups. Xanthine (100 microM) and xanthine oxidase (0.02 U/ml) applied for 1 or 6h reduced the viability of cells at 8 div assessed using the alamar blue assay, and induced morphological changes, such as shrinkage of the cell bodies and neurites. Heat-inactivation of xanthine oxidase resulted in complete loss of its activity. Superoxide dismutase (250 U/ml) failed to modify the damage by xanthine and xanthine oxidase, while catalase (250 U/ml) completely prevented it. When applied alone, xanthine oxidase significantly lowered cell viability, an effect that was blocked by allopurinol and catalase, but not by superoxide dismutase. The results indicate that xanthine and xanthine oxidase can produce predominantly hydrogen peroxide instead of the superoxide anion. Cerebellar granule cells in culture may also possess significant levels of endogenous xanthine.
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PMID:Hydrogen peroxide mediates damage by xanthine and xanthine oxidase in cerebellar granule neuronal cultures. 1736 Jan 18


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