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At least 721 records · Page 40Linked to original sources
PubMed2006

ROS-sensitive cytochrome P450 activity maintains endothelial dilatation in ageing but is transitory in dyslipidaemic mice.

Risk factors for cardiovascular diseases (CVD) have been proposed to accelerate the vascular endothelial dysfunction that develops during the normal ageing process. The objective of this work was to study the impact of dyslipidaemia (DL) on the dilatory efficacy of the non-NO/non-PGI2 endothelium-derived hyperpolarising factor (EDHF) through maturation and ageing. We isolated and pressurised (80 mmHg) gracilis arterial segments from 3, 12 and 20-month-old (m/o) DL mice expressing the human apolipoprotein B-100 and wild-type (WT) C57BL/6 mice. EDHF-dependent dilatations to acetylcholine (ACh) were measured in the presence of L-NNA (100 microM, NOS inhibitor) and indomethacin (INDO; 10 microM, COX inhibitor). Data are expressed as mean+/-s.e.m.EDHF-mediated maximal dilatation of arteries isolated from WT mice declined by 44% with ageing, from 86+/-3% at 3 months to 66+/-8% at 12 and 48+/-4% at 20 months of age (P<0.05). This decline was magnified by DL to 73%, characterised by an early increased efficacy at 3 m/o (95+/-2%, P<0.05) and a worsening of the dysfunction at 20 m/o (26+/-2%, P<0.05). 17-Octadecynoic acid (17-ODYA), a cytochrome P450/epoxygenase inhibitor, reduced by 56% (P<0.05) ACh-induced EDHF-dependent dilatation of arteries isolated from 3 m/o DL--but not WT--mice, an effect of 17-ODYA disappearing in older DL mice. 17-ODYA, however, reduced (P<0.05) ACh-induced EDHF-dependent dilatation in arteries isolated from 12 m/o WT mice by 35% and from 20 m/o WT mice by 31% (P<0.05). Reactive oxygen species production was increased in arteries isolated from 12 m/o DL mice. The antioxidant N-acetyl-L-cystein (NAC) restored the 17-ODYA-sensitive responses in arteries isolated from 12 - but not 20 - m/o DL mice (84+/-3% from an E(max) of 57+/-8%; P<0.05). NAC did not affect the dilatation of arteries isolated from WT mice. Our data suggest that the decline in EDHF-dependent dilatation is hastened by DL despite the early expression of a 17-ODYA-sensitive pathway increasing the efficacy of the non-NO/non-PGI2 endothelium-dependent dilatation. Acute free radical production contributes to the endothelial dysfunction in the presence of DL only, by abrogating this latter pathway. This 17-ODYA-sensitive pathway, however, appears in 12 m/o WT mice and remains active at 20 m/o.

Acetylcholine↗
PubMed2006

Novel 6-formylpterin derivatives: chemical synthesis and O2 to ROS conversion activities.

6-Formylpterin (6FP) has been demonstrated to have strong neuroprotective effects against transient ischemia-reperfusion injury in gerbils. Also it has been shown that in rats, 6FP protected retinal neurons even when it was administered after the ischemic insult. Since there is a significant need for such a compound that effectively suppresses the events caused by the lack of oxygen supply, 6FP has attracted further investigation. Unfortunately, however, 6FP is hardly soluble in water at neutral pH and in organic solvents because of its self-assembling ability. Although a several mM solution of 6FP is available in alkaline water, it is unstable. In the present study, a novel chemical derivatization of 6FP has been developed which maintains the formyl group on the 6-position of 6FP, which is essential for the physiological activities of 6FP, and increases solubility in water and organic solvents. In the method, the 2- and 3-positions of 6FP were modified by a three component coupling reaction: 6FP was subjected to the reaction with acid chloride and N,N-dimethylformamide. The derivatives synthesized here, 2-(N,N-dimethylaminomethyleneamino)-6-formyl-3-pivaloylpteridine-4-one 1, 2-(N,N-dimethylaminomethyleneamino)-6-formyl-3-isobutyrylpteridine-4-one 2, and 2-(N,N-dimethylaminomethyleneamino)-6-formyl-3-o-toluoylpteridine-4-one 3, showed high solubility in water (1.0-5.6 mM) and organic solvents. The O(2) conversion property has also been determined for the derivative 1. Using an oxygen electrode, it has been found that O(2) is consumed in the presence of 1 and NADH at around pH 7.4 and that the rate of O(2) consumption is enhanced by UV-A irradiation. Electron paramagnetic resonance (EPR) analysis coupled with DMPO spin trapping has also revealed that in the presence of NADH, 1 converts O(2) to O(2)(-), which is further reduced to OH. By UV-A illumination in the analogous systems, (1)O(2) formation was observed. These results are similar to those reported previously for 6FP.

Electrodes↗
PubMed2004

Hypoxic remodelling of Ca2+ mobilization in type I cortical astrocytes: involvement of ROS and pro-amyloidogenic APP processing.

Chronic hypoxia (CH) alters Ca2+ homeostasis in various cells and may contribute to disturbed Ca2+ homeostasis of Alzheimer's disease. Here, we have employed microfluorimetric measurements of [Ca2+]i to investigate the mechanism underlying augmentation of Ca2+ signalling by chronic hypoxia in type I cortical astrocytes. Application of bradykinin evoked significantly larger rises of [Ca2+]i in hypoxic cells as compared with control cells. This augmentation was prevented fully by either melatonin (150 micro m) or ascorbic acid (200 micro m), indicating the involvement of reactive oxygen species. Given the association between hypoxia and increased production of amyloid beta peptides (AbetaPs) of Alzheimer's disease, we performed immunofluorescence studies to show that hypoxia caused a marked and consistent increased staining for AbetaPs and presenilin-1 (PS-1). Western blot experiments also confirmed that hypoxia increased PS-1 protein levels. Hypoxic increases of AbetaP production was prevented with inhibitors of either gamma- or beta-secretase. These inhibitors also partially prevented the augmentation of Ca2+ signalling in astrocytes. Our results indicate that chronic hypoxia enhances agonist-evoked rises of [Ca2+]i in cortical astrocytes, and that this can be prevented by antioxidants and appears to be associated with increased AbetaP formation.

Alzheimer Disease↗
PubMed2006

ROS production and angiogenic regulation by macrophages in response to heat therapy.

PURPOSE: It has been well established that inadequate blood supply combined with high metabolic rates of oxygen consumption results in areas of low oxygen tension (<1%) within malignant tumours and that elevating tumour temperatures above 39 degrees Celsius results in significant improvement in tumour oxygenation. Macrophages play a dual role in tumour initiation and progression having both pro-tumour and anti-tumour effects. However, the response of macrophages to heat within a hypoxic environment has not yet been clearly defined. METHODS: Raw 264.7 murine macrophages were incubated under normoxia and chronic hypoxia at temperatures ranging from 37-43 degrees Celsius. Under normoxia at 41 degrees Celsius, macrophages start to release significant levels of superoxide. The combination of heat with hypoxia constitutes an additional stimulus leading to increased respiratory burst of macrophages. RESULTS: The high levels of superoxide were found to be associated with changes in macrophage production of pro-angiogenic cytokines. While hypoxia alone (37 degrees Celsius) increased levels of hypoxia inducible factor-1alpha (HIF-1alpha) in macrophages, the combination of hypoxia and mild hyperthermia (39-41 degrees Celsius) induced a strong reduction in HIF-1alpha expression. The HIF-regulated vascular endothelial growth factor (VEGF) decreased simultaneously, revealing that heat inhibits both HIF-1alpha stabilization and transcriptional activity. CONCLUSION: The data suggest that temperatures which are readily achievable in the clinic (39-41 degrees Celsius) might be optimal for maximizing hyperthermic response. At higher temperatures, these effects are reversed, thereby limiting the therapeutic benefits of more severe hyperthermic exposure.

Animals↗
PubMedDate not supplied

Early involvement of ROS overproduction in apoptosis induced by 7-ketocholesterol.

Cholesterol oxidation products are increasingly considered as much more bioactive than the parent compound in the multifactor and multistep process that characterizes atherosclerosis. In particular, 7-ketocholesterol has been reported to induce oxidative stress as well as a marked pro-apoptotic effect in vascular cells including macrophages. With the aim to investigate a possible pathogenic correlation between the two events, cultivated murine macrophages were challenged with a concentration of 7-ketocholesterol actually detectable in human vasculature. Conclusive proof was obtained of a primary role of NADPH-oxidase in the overproduction of reactive oxygen species within cells treated with the oxysterol. In addition, such oxidative burst occurred very early after cell intoxication and it was definitely demonstrated as able to lead cells to apoptotic death. In fact, two metabolic inhibitors of NADPH-oxidase and the antioxidant epicatechin very well counteracted 7-ketocholesterol-induced apoptosis by preventing the oxysterol pro-oxidant action.

Animals↗
PubMed2004

CPTF1, a CREB-like transcription factor, is involved in the oxidative stress response in the phytopathogen Claviceps purpurea and modulates ROS level in its host Secale cereale.

CPTF1, a transcription factor with significant homology to ATF/CREB bZIP factors, was identified during an expressed sequence tag (EST) analysis of in planta-expressed genes of the phytopathogen Claviceps purpurea. Using a gene-replacement approach, deletion mutants of cptf1 were created. Expression studies in axenic culture showed that the H2O2-inducible gene cpcat1 (encoding a secreted catalase) had a reduced basal expression level and no longer responded to oxidative stress in the delta cptf1 mutant. Biochemical analyses indicated that CPTF1 is a general regulator of catalase activity. Delta cptf1 mutants showed significantly reduced virulence on rye. Electron microscopical in situ localization revealed significant amounts of H2O2 in delta cptf1-infected rye epidermal tissues, indicating that the plant tissue displayed an oxidative burst-like reaction, an event not detected in wild-type infections. These data indicate that CPTF1 is involved not only in oxidative stress response in the fungus but also in modulation of the plant's defense reactions.

Amino Acid Sequence↗
PubMed1999

Glutamate triggers preferential Zn2+ flux through Ca2+ permeable AMPA channels and consequent ROS production.

ZN2+ co-released with glutamate at excitatory synaptic sites can enter and cause injury to postsynaptic neurons. While prior studies using the slowly desensitizing agonist kainate suggested preferential Zn2+ permeation through Ca2+ permeable AMPA/kainate (Ca-A/K) channels, the present study aims to assess relevance of those findings upon more physiological receptor activation. Microfluorimetric techniques were used to measure [Zn2+]i attained upon exposure to the rapidly desensitizing agonist AMPA or to the physiological agonist glutamate, in the presence of 300 microM Zn2+. Under these conditions, micromolar [Zn2+]i rises (delta[Zn2+]i) were still observed to occur selectively in the subset of neurons that express large numbers of Ca-A/ K channels. Further studies using the oxidation sensitive dye, hydroethidine, revealed Zn2+-dependent reactive oxygen species generation that paralleled delta[Zn2+]i, with rapid oxidation only observed in the case of Zn2+ entry through Ca-A/K channels.

Animals↗
PubMed2005

A central role for ROS in the functional remodelling of L-type Ca2+ channels by hypoxia.

Periods of prolonged hypoxia are associated clinically with an increased incidence of dementia, the most common form of which is Alzheimer's disease. Here, we review recent studies aimed at providing a cellular basis for this association. Hypoxia promoted an enhanced secretory response of excitable cells via formation of a novel Ca2+ influx pathway associated with the formation of amyloid peptides of Alzheimer's disease. More strikingly, hypoxia potentiated Ca2+ influx specifically through L-type Ca2+ channels in three distinct cellular systems. This effect was post-transcriptional, and evidence suggests it occurred via increased formation of amyloid peptides which alter Ca2+ channel trafficking via a mechanism involving increased production of reactive oxygen species by mitochondria. This action of hypoxia is likely to contribute to dysregulation of Ca2+ homeostasis, which has been proposed as a mechanism of cell death in Alzheimer's disease. We suggest, therefore, that our data provide a cellular basis to account for the known increased incidence of Alzheimer's disease in patients who have suffered prolonged hypoxic episodes.

Amyloid↗
PubMed1991

Skin inflammation induced by reactive oxygen species (ROS): an in-vivo model.

A model of skin inflammation induced by reactive oxygen species has been established using the hydrogen-peroxide-producing enzyme glucose oxidase. As a means of increasing the half-life of the enzyme and tissue retention polyethylene glycol (PEG) was attached. A rapid inflammatory response occurred consisting of an oedematous, non-erythemic swelling lasting at least 48 h. Histologically, there was an infiltration of the dermis by monocytes and neutrophils, collagen matrix breakdown and damage to the vascular endothelium. This response was significantly inhibited by both catalase and superoxide dismutase attached to PEG (PEG-CAT and PEG-SOD, respectively). PEG alone produced no effects. PEG-CAT was able to sustain an inhibitory effect for at least 12 h, whereas PEG-SOD significantly reduced inflammation for up to 6 h. PEG-SOD may have an exacerbatory effect over longer periods.

Animals↗