Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac dysfunction after cardiopulmonary bypass (CPB) has been reported by various investigators. Oxygen free radicals have been shown to depress cardiac function and contractility. To evaluate the possible role of oxygen free radicals (OFR) in post-pump cardiac dysfunction, measurements of cardiac function, OFR producing activity of polymorphonuclear (PMN) leukocytes (PMN chemiluminescence) and malondialdehyde (MDA), a lipid peroxidation product, in blood were made at induction of anesthesia (T1), before cross clamping of the aorta (T2), after closure of the chest (T3), and 24 hours postoperatively (T4) in 21 patients undergoing aortocoronary bypass surgery. The total OFR-derived chemiluminescence at T1, T2, T3, and T4 was 1590 +/- 156, 3169 +/- 338, 1972 +/- 214, and 2614 +/- 366 mv.min.10(6) PMN-1, respectively. Superoxide dismutase (SOD)-inhibitable chemiluminescence at T1, T2, T3, and T4 was 1214 +/- 129, 2674 +/- 328, 1752 +/- 215, and 2139 +/- 292 mv.min.10(6) PMN-1, respectively. Superoxide anion at T1, T2, T3, and T4 was 0.99 +/- 0.14, 1.30 +/- 0.17, 1.07 +/- 0.14, and 1.19 +/- 0.12 nmol.10(6) PMN-1.30 min-1, respectively. Blood MDA at T1, T2, T3, and T4 was 0.17 +/- 0.02, 0.25 +/- 0.03, 0.20 +/- 0.03, and 0.23 +/- 0.02 nmol/ml, respectively. OFR-derived and SOD inhibitable chemiluminescence, superoxide anion, and blood MDA increased significantly during CPB and postoperatively. There were decreases in the blood pressure and stroke volume, and increases in the central venous pressure, capillary wedge pressure, and heart rate during CPB and postoperatively. Cardiac output remained unchanged during this procedure. There was leukopenia during CPB.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increased oxygen free radical activity in patients on cardiopulmonary bypass undergoing aortocoronary bypass surgery. 130 23

Heme oxygenase (HO) is believed to be a potent antioxidant enzyme in the nervous system; it degrades heme from heme-containing proteins, giving rise to carbon monoxide, iron, and biliverdin, which is rapidly reduced to bilirubin. The first identified isoform of the enzyme, HO1, is an inducible heat-shock protein expressed in high levels in peripheral organs and barely detectable under normal conditions in the brain, whereas HO2 is constitutive and most highly concentrated in the brain. Interestingly, although HO2 is constitutively expressed, its activity can be modulated by phosphorylation. We demonstrated that bilirubin, formed from HO2, is neuroprotectant, as neurotoxicity is augmented in neuronal cultures from mice with targeted deletion of HO2 (HO2(-/-)) and reversed by low concentrations of bilirubin. We now show that neural damage following middle cerebral artery occlusion (MCAO) and reperfusion, a model of focal ischemia of vascular stroke, is substantially worsened in HO2(-/-) animals. By contrast, stroke damage is not significantly altered in HO1(-/-) mice, despite their greater debility. Neural damage following intracranial injections of N-methyl-d-aspartate (NMDA) is also accentuated in HO2(-/-) animals. These findings establish HO2 as an endogenous neuroprotective system in the brain whose pharmacologic manipulation may have therapeutic relevance.
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PMID:Heme oxygenase-2 is neuroprotective in cerebral ischemia. 1060 74

Free radical are highly reactive chemical species with an unpaired electron in an atomic or molecular orbital. In biological systems, the most important free radicals are superoxide anion and hydrogen peroxide; in the presence of transition metals such as iron, copper and manganese both these free radicals produce hydroxyl radicals. Free radicals attack proteins, nuclei acids and membranes containing large quantities of polyunsaturated fatty acids. Because of their toxicity, the organism has developed ways to deactivate them. The superoxide dismutase enzyme (SOD) catalyzes dismutation of the superoxide radical into hydrogen peroxide and oxygen hydrogen peroxide is in turn reduced to water and oxygen by peroxidase glutathione and catalase enzymes. The production of radicals in the brain is due to catecholamine metabolism such as dopamine and norepinephrine and is increased by the presence of transition metals and by a deficiency of antioxidant agents such as vitamin E. Two main groups of dementia exist in older age: the multi-infarctual dementias, caused by cerebrovascular disorders and the primary degenerative disorders such as Alzheimer, where no vascular disease is evident. Free radicals play an important role in Parkinson's disease, in Alzheimer's disease and in stroke. The value of SOD and CAT activity following the above mentioned degenerative diseases differ among the various studies carried out. In Alzheimer's disease, the value of SOD activity probably increases in the neuropathologically involved areas. In stroke, the SOD value does not vary either in the ischemic area or in the peri-infarctual one during the first 24 hrs after lesion, while the CAT value decreases.
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PMID:Free radicals: important cause of pathologies refer to ageing. 1070 16

The generation of oxygen radicals and lipid peroxidation may be factors in the cerebral damage secondary to ischaemia of the cerebrovascular disease, as in stroke. Five traditional Chinese medicinal prescriptions were investigated for their antioxidant activity: Shiee Fuu Jwu Iu Tang (TCMP1), Oh Yaw Shuen Chin Saan (TCMP2), Buu Yang Hwan Wuu Tang (TCMP3), Sheau Shiuh Ming Tang (TCMP4), and Chir Hwu Jia Long Guu Muu Lih Tang (TCMP5). Anti-lipid peroxidation, anti-superoxide formation and free radical scavenger activity were determined by the FeCl2--ascorbic acid-induced lipid peroxidation effects on lipids in-vitro, xanthine oxidase inhibition, cytochrome C system and an electron spin resonance spectrometer, respectively. The results showed that TCMP5 had greater anti-lipid peroxidation and anti-superoxide formation activity than the other prescriptions. TCMP4 had the greatest free radical scavenging effect, TCMP5 showed the greatest superoxide radical scavenger activity and TCMP3 showed the greatest hydroxyl radical scavenger activity. Tests were also performed to evaluate the effects of the five prescriptions on blood lipid in-vivo. The test showed that the prescriptions decreased the level of total cholesterol and LDL-cholesterol in serum in high cholesterol-fed rats. From these results, it seems probable that these prescriptions may be effective in the prevention and therapy of stroke and ischaemia.
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PMID:Anti-hypercholesterolaemia, antioxidant activity and free radical scavenger effects of traditional Chinese medicine prescriptions used for stroke. 1118 47

There is evidence in humans that hypertension and aging similarly impair endothelial function, although the mechanism remains unclear. Superoxide anion (O(2)(-)) is a major determinant of nitric oxide (NO) bioavailability and thus endothelial function. We sought to determine the relationship between endothelial function, O(2)(-), and age in normotensive Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Aortic rings were removed from female WKY and SHRSP at 3 to 4 months (young) and 9 to 12 months (old). O(2)(-) generation by aortic rings was measured before and after removal of the endothelium or incubation with N(G) nitro-L-arginine methyl ester, diphenyleneiodonium, or apocynin. Levels of p22phox were studied with immunohistochemistry and used as a marker of NAD(P)H oxidase expression. NO bioavailability was significantly lower in old WKY compared with young WKY (P=0.0009) and in old SHRSP compared with young SHRSP (P=0.005). O(2)(-) generation was significantly greater in old WKY compared with young WKY (P=0.0001). Removal of the endothelium and N(G) nitro-L-arginine methyl ester treatment resulted in a significant reduction in O(2)(-) generation in old SHRSP (P=0.009 and 0.001, respectively). Diphenyleneiodonium significantly reduced O(2)(-) generation in 12-month WKY (P=0.008) and 12-month SHRSP (P=0.009). Apocynin attenuated O(2)(-) generation by older WKY (P=0.038) and SHRSP (P=0.028). p22phox was increased in older animals compared with young. We conclude that NO bioavailability decreases with age in female WKY and SHRSP. O(2)(-) generation increases with age in WKY and is higher in SHRSP and may contribute to the reduced NO by scavenging. NAD(P)H oxidase may contribute to the age-related increase in O(2)(-).
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PMID:Superoxide excess in hypertension and aging: a common cause of endothelial dysfunction. 1123 Mar 30

Bed rest is an integral part of treatment of numerous diseases. Typical examples are bone fractures of lower extremities and pelvis. Temporary immobilization is necessary also, e.g., in heart diseases (stroke), backbone and imminent abortion. The sick organism spares energy during the bed rest wich is beneficial. However, bed rest results in many alterations which are disadavantageous. They concern the function of almost all organs and systems but affect most significantly the locomotor and ciruclatory systems. Bed rest brings also about changes in the composition of peripheral blood and functions of the morphotic elements of blood. Red blood cells are subjected to the action of large amounts of reactive oxygen species (ROS). During oxidation of hemoglobin to methemoglobin superoxide radical anion (O2-) is formed: HbFe2+ + O2 --> MetHbFe3+ + O2- (1) Ferrous and ferric ions present in the cytoplasm of red blood cells may be catalysts of the Fenton reaction leading to the production of the hydroxyl radical: O2- + Fe3+ --> O2- + Fe2+ (2) Fe2+ + H2O2 --> Fe3+ + OH + HO- (3) OH shows a tremendous reactivity. It may react with lipids, proteins, nucleic acids and carbohydrates. The process of lipid peroxidation is best understood. It concerns mainly polyunsaturated fatty acids present in cell membranes. Peroxidation of membrane lipids decreases membrane fluidity and impairs its barrier function. The lowered membrane fluidity compromises erythrocyte deormability which in turn disturbs oxygen delivery to the tissues. End productions of lipid peroxidation are low-molecular wieght compounds, among them carbohydrates (ethane and pentane) and aldehydes, e.g. malondialdehyde (MDA). MDA concentration is an acknowldeged marker of the intensity of lipid peroxidation. Erythrocytes contain a complex system of protection against the action of ROS. It includes various enzymatic and non-enzymatic mechanism. The most important antioxidative enzymes of the red blood cells are superoxide dismutase (Cu,Zn-SOD, EC 1.15.1.1) catalase (CAT, EC 1.11.1.6) and glutathione peroxidase (GSH-Px, EC 1.11.1.9). Cu,Zn-SOD catalyzes the dismuation of O2- to hydrogen peroxide (H2O2). Catalase and peroxidase remove H2O2 and, moreover, GSH-Px can reduce lipid peroxides. Under normal conditions an equilibrium exists between the formation and removal ROS. If ROS are formed in excess or the defensive antioxidative mechanism are inefficient, oxidative stress develops. Derangement of the equilibrium between the formation and removal of ROS is important in the pathosgenesis of many diseases, e.g. atherosclerosis, diabetes, Down syndrome and Alzheimer disease. There are literature data on disturbances of enzymatic antioxidant defense mechanism of blood plateless during bed rest. This study was aimed at an examination of the post-traumatic bed rest on the enzymatic antioxidative defense mechanisms and lipid peroxidation in erythrocytes.
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PMID:Effect of long term bed rest in men on enzymatic antioxidative defence and lipid peroxidation in erythrocytes. 1154 39

The heme oxygenase (HO) and nitric oxide (NO) synthase (NOS) systems display notable similarities as well as differences. HO and NOS are both oxidative enzymes using NADPH as an electron donor. The constitutive forms of the enzyme are differentially activated, with calcium entry stimulating NOS by binding to calmodulin, whereas calcium entry activates protein kinase C to phosphorylate and activate HO2. Although both NO and carbon monoxide (CO) stimulate soluble guanylyl cyclase to form cGMP, NO also S-nitrosylates selected protein targets. Both involve constitutive and inducible biosynthetic enzymes. However, functions of the inducible forms are virtual opposites. Macrophage-inducible NOS generates NO to kill other cells, whereas HO1 generates bilirubin to exert antioxidant cytoprotective effects and also provides cytoprotection by facilitating iron extrusion from cells. The neuronal form of HO, HO2, is also cytoprotective. Normally, neural NO in the brain seems to exert some sort of behavioral inhibition. However, excess release of NO in response to glutamate's N-methyl-d-aspartate receptor activation leads to stroke damage. On the other hand, massive neuronal firing during a stroke presumably activates HO2, leading to neuroprotective actions of bilirubin. Loss of this neuroprotection after HO inhibition by mutant forms of amyloid precursor protein may mediate neurotoxicity in Familial Alzheimer's Disease. NO and CO both appear to be neurotransmitters in the brain and peripheral autonomic nervous system. They also are physiologic endothelial-derived relaxing factors for blood vessels. In the gastrointestinal pathway, NO and CO appear to function as coneurotransmitters, both stimulating soluble guanylyl cyclase to cause smooth muscle relaxation.
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PMID:Neural roles for heme oxygenase: contrasts to nitric oxide synthase. 1157 59

The sequential univalent reduction of oxygen generates superoxide, hydrogen peroxide, and hydroxyl radical. The generation of hydroxyl radical is dependent on catalysis by ferrous iron. In addition, superoxide and nitric oxide produce peroxynitrite, which spontaneously generates hydroxyl radical independently of iron-mediated catalysis. These agents have a variety of cellular actions, which render them suitable candidates as mediators of tissue destruction and cellular death. In the intact brain, superoxide and its derivatives cause vasodilation, mediated by opening of potassium channels, altered vascular reactivity, breakdown of the blood-brain barrier, and focal destructive endothelial lesions. These abnormalities are also seen in early reperfusion following brain ischemia. During reperfusion there is a marked transient increase in superoxide production. Vasodilation, abnormal vascular reactivity, and blood-brain barrier breakdown are inhibited by eliminating superoxide. Superoxide production during reperfusion may be initiated by glutamate via activation of alpha-amino-3-hydroxy-5-methylisoxasolepropionic acid (AMPA) receptors. These experimental findings have important implications for human cerebral ischemia. Agents directed at eliminating oxygen radicals must be administered before or in the early stages of reperfusion following ischemia. The therapeutic window appears to be narrow and limited to, at most, a few hours. The inhibition of AMPA receptors may be a promising approach to inhibit the production of oxygen radicals during ischemia-reperfusion of the brain.
Stroke 2001 Nov
PMID:Oxygen radicals in cerebral ischemia: the 2001 Willis lecture. 1169 43

Superoxide production via NADPH oxidase has been shown to play a role in neurotoxicity, ischemic stroke, and possibly Parkinson's and Alzheimer's diseases. In addition, NADPH oxidase-dependent production of superoxide may be necessary for normal brain functions, including neuronal differentiation and neuronal plasticity. To improve our understanding of NADPH oxidase in the brain, we studied the localization of the various protein components of NADPH oxidase in the central nervous system of the adult mouse using immunohistochemistry. We detected staining for the cytoplasmic NADPH proteins, p40(phox), p47(phox), and p67(phox), as well as the membrane-associated NADPH oxidase proteins, p22(phox) and gp91(phox) in neurons throughout the mouse brain. Staining of each of the NADPH oxidase proteins was observed in neurons in all regions of the neuraxis, with particularly prominent localizations in the hippocampus, cortex, amygdala, striatum, and thalamus. The expression of NADPH oxidase proteins in neurons suggests the possibility that enzymatic production of superoxide by a NADPH oxidase may play a role in both normal neuronal function as well as neurodegeneration in the brain.
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PMID:NADPH oxidase immunoreactivity in the mouse brain. 1451 42

The brain is deficient in oxidative defense mechanisms and hence is at greater risk of damage mediated by reactive oxygen species (ROS) resulting in molecular and cellular dysfunction. Emerging evidence suggesting the activation of glutamate gated cation channels, may be another source of oxidative stress, leading to neuronal degeneration. Oxidative stress has been implicated in the development of neurodegenerative diseases like Parkinsonism, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, epileptic seizures, and stroke. Melatonin, the pineal hormone, acts as a direct free radical scavenger and indirect antioxidant. It is suggested that the increase in neurodegenerative diseases is attributable to a decrease in the levels of melatonin with age. Melatonin has been shown to either stimulate gene expression for the antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase) or to increase their activity. Additionally, it neutralizes hydoxyl radical, superoxide radical, peroxyl radical, peroxynitrite anion, singlet oxygen, hydrogen peroxide, nitric oxide, and hypochlorous acid. Unlike other antioxidants, melatonin can easily cross all morphophysiological barriers, e.g., the blood brain barrier, and enters cells and subcellular compartments. Though evidence are accumulating to suggest the potential of melatonin in neurodegenerative conditions, much information needs to be generated before the drug can find place in neurology clinics.
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PMID:Neuroprotective role of melatonin in oxidative stress vulnerable brain. 1526 48


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