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Biomedical subjects

J M Gutteridge

Publications and source records attributed to J M Gutteridge.

At least 55 records · Page 3Linked to original sources
PubMed1995

Prooxidant iron and copper, with ferroxidase and xanthine oxidase activities in human atherosclerotic material.

Low density lipoproteins are highly sensitive to oxidation by copper salts, and such peroxidation is accompanied by macrophage scavenger receptor recognition. This study shows that fresh human atherosclerotic material (aneurysms and endarterectomies) can contain detectable amounts of redox active iron and copper that is chelatable from tissue homogenates. Such material is often prooxidant towards lipid peroxidation and deoxyribose degradation. Aneurysms and endarterectomies contain ferroxidase 1 activities, whereas only in aneurysms could caeruloplasmin be immunologically detected. Ferroxidase 2 activity, characteristic of a copper-oxidised lipoprotein complex, could not, however, be detected in any of the atherosclerotic samples. A third ferroxidase activity, attributable to xanthine oxidase, was present in several aneurysms and endarterectomies.

Arteriosclerosis↗
PubMed1995

Blood cardioplegia increases plasma iron overload and thiol levels during cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass and crossclamping of the ascending aorta introduce two well-characterized phases of oxidative stress, namely, the extracorporeal circulation of blood and the reoxygenation of ischemic tissue. A feature of both forms of stress is the release of reactive and damaging oxygen species. METHODS: Forty-seven patients undergoing aortic valve replacement received either cold crystalloid, cold blood, or warm blood cardioplegia. Plasma thiol levels were measured in all groups before and during bypass. All cardiopulmonary bypass patients had, before going onto bypass, low plasma thiol levels (3.80 +/- 0.22 nmol/mg protein) compared with normal healthy controls (5.48 +/- 0.14 nmol/mg protein). RESULTS: Thiol values remained low throughout bypass in patients receiving cold crystalloid cardioplegia, but rose in patients receiving cold blood cardioplegia, and rose even more in patients receiving warm blood cardioplegia to reach normal plasma values. During cardiopulmonary bypass it has previously been reported that plasma transferrin can become fully saturated with iron and cause transient iron overload. Two patients (13%) receiving cold crystalloid cardioplegia went into plasma iron overload, whereas 18% receiving cold blood and 27% receiving warm blood cardioplegia showed plasma iron overload. CONCLUSIONS: We suggest that blood cardioplegia provides an additional source of thiols as well as a source of reactive iron. However, the reactive iron and thiol-containing molecules have the potential to interact and exacerbate oxidative stress, already a feature of bypass. Control of reactive iron by chelation may be strongly indicated when blood cardioplegia is used.

Adult↗
PubMed1995

Ferrous ions detected in iron-overloaded cord blood plasma from preterm and term babies: implications for oxidative stress.

Redox active iron chelatable to bleomycin is often present in the plasma of cord blood samples taken from preterm and term babies. The low caeruloplasmin and high ascorbate levels in plasma at birth may allow this iron to exist in the reduced ferrous state. In support of this postulate thirteen cord blood samples showing the presence of low molecular mass iron were able to degrade DNA in the presence of bleomycin and plasma.

Bleomycin↗
PubMed1995

Lipid peroxidation and antioxidants as biomarkers of tissue damage.

Disturbance of the balance between the production of reactive oxygen species such as superoxide; hydrogen peroxide; hypochlorous acid; hydroxyl, alkoxyl, and peroxyl radicals; and antioxidant defenses against them produces oxidative stress, which amplifies tissue damage by releasing prooxidative forms of reactive iron that are able to drive Fenton chemistry and lipid peroxidation and by eroding away protective sacrificial antioxidants. The body has a hierarchy of defense strategies to deal with oxidative stress within different cellular compartments, and superimposed on these are gene-regulated defenses involving the heat-shock and oxidant stress proteins.

Antioxidants↗
PubMed1994

Peroxynitrite releases copper from caeruloplasmin: implications for atherosclerosis.

Peroxynitrite may be formed in the vasculature by the reaction of superoxide with nitric oxide. When the blue copper-containing protein, caeruloplasmin, is incubated with peroxynitrite, copper is released, and ferroxidase activity and the blue colouration are lost. When plasma from normal subjects is incubated with peroxynitrite, the oxidant reacts with numerous plasma constituents but is still able to release copper from caeruloplasmin. As the ferroxidase activity of caeruloplasmin is lost in plasma in the presence of peroxynitrite, a second ferroxidase activity associated with peroxidised lipids, and not inhibited by azide, is formed.

Arteriosclerosis↗
PubMed1994

Biological origin of free radicals, and mechanisms of antioxidant protection.

Reduced intermediates of molecular oxygen, such as superoxide and hydrogen peroxide, are ubiquitous inorganic products of normal aerobic metabolism. Certain cells, such as phagocytes, have evolved to use superoxide and hydrogen peroxide for purposeful chemistry beneficial to the host, but most cells require antioxidant protection against excessive production of these intermediates. Superoxide and hydrogen peroxide are themselves poorly reactive in aqueous solution, and unable to directly damage DNA, lipids and proteins. Excessive generation, however, of superoxide and hydrogen peroxide invariably accompanies molecular damage. Substantial evidence suggests that conversion of these poorly reactive intermediates of oxygen to highly reactive forms requires the participation of transition metal ions, particularly iron. Iron ions react with hydrogen peroxide (Fenton chemistry) to generate hydroxyl radicals that can damage all organic molecules.

Antioxidants↗
PubMed1994

Ferrous ion formation by ferrioxamine prepared from aged desferrioxamine: a potential prooxidant property.

The siderophore desferrioxamine (DEFOM) binds ferric ions in a 1:1 ratio resulting in a ferrioxamine (FOM) complex. When DEFOM is stored or heat degraded, the resulting FOMD undergoes an autoreduction with the transfer of electrons to the bound ferric ions forming ferrous ions which react with Ferrozine to yield a pink-coloured complex absorbing at 562 nm. Heat-aged DEFOM forms a FOMD complex with an absorption maxima changing from 432 nm to 441 nm. When the autoreduced FOMD complex is placed in a phosphate buffer at pH 7.4, ferrous ions autoxidise transferring electrons to molecular oxygen to form superoxide and hydrogen peroxide. Fenton chemistry leading to the formation of hydroxyl radicals can then occur. Studies with a variety of reactive oxygen scavengers support a role for the hydroxyl radical in damage to the detector molecule deoxyribose. However, when EDTA is present, damage to deoxyribose is decreased and the radicals causing deoxyribose degradation no longer appear to be characteristic of the hydroxyl radical.

Deferoxamine↗
PubMed1994

Transient iron overload with bleomycin detectable iron in the plasma of patients with adult respiratory distress syndrome.

BACKGROUND: A retrospective study was conducted to evaluate iron status in plasma samples collected from five patients with the adult respiratory distress syndrome (ARDS) who had bleomycin detectable iron in at least one sample. Ten patients with ARDS with no evidence of bleomycin detectable iron and 10 healthy individuals served as controls. METHODS: Evidence of iron overload was established by measuring the percentage saturation of plasma transferrin. In each case the bleomycin assay for redox active, chelatable iron was used to measure plasma levels of non-transferrin bound iron in the low micromolar range; assays for total plasma iron and transferrin were performed to establish a diagnosis of transient iron overload. The effect of this on the ability of transferrin to act as a plasma antioxidant was assessed using two different assay systems. RESULTS: The five patients with evidence of transient iron overload (mortality 4/5) represented 33% of the total population of patients with ARDS (mortality 5/10) managed by the unit during the study period. All had low molecular mass iron detectable in their plasma and had clinical and biochemical evidence of multiorgan system failure as well as liver impairment. Compared with the ARDS and normal control populations, transferrin and albumin levels were low and the former failed to act as a plasma antioxidant in preventing free radical mediated damage to detector molecules. CONCLUSIONS: Patients with ARDS are thought to be under severe oxidative stress from their disease and from treatment with high inspired oxygen concentrations. A subgroup of patients with ARDS has been identified who displayed evidence of transient iron overload as a result of which their plasma iron binding antioxidant protection was greatly compromised. This finding must be considered a serious additional risk factor for oxidative stress.

Adult↗
PubMed1994

Transient iron-overload with bleomycin-detectable iron present during cardiopulmonary bypass surgery.

Extracorporeal circulation of blood during cardiopulmonary bypass surgery exposes cells to non-physiological surfaces and shear stress which can activate several regulatory cascades, and neutrophils to release superoxide and hydrogen peroxide. Shear stresses generated by pumps and suction systems cause lysis of red blood cells and the release of haemoglobin. Together the release of reactive forms of oxygen and haemoglobin can lead to the appearance of low molecular mass chelatable iron (bleomycin-detectable iron). All patients undergoing open heart surgery appear to release iron to plasma transferrin, increasing its iron saturation. In 13% of patients, however, the transferrin became fully iron-saturated, and by the end of open-heart surgery we could detect bleomycin-chelatable iron in the plasma. Saturation of transferrin with iron eliminates its iron-binding antioxidant properties, which can result in a stimulation of iron-dependent radical damage to selected detector molecules.

Adult↗
PubMed1994

4-hydroxy-2-nonenal levels increase in the plasma of patients with adult respiratory distress syndrome as linoleic acid appears to fall.

Gas chromatograph-mass spectrometry has been applied to the analysis of plasma linoleic acid and one of its oxidation products, 4-hydroxy-2-nonenal (HNE), in adult patients with the acute respiratory distress syndrome (ARDS). Peak areas of total ion chromatograms showed there to be negative correlations between loss of linoleic acid and formation of HNE (measured by selective ion monitoring) in 7 out 10 patients studied. When HNE was quantitated by selective ion monitoring, with reference to a pure standard of HNE and an internal standard of nonanoic acid, ARDS patients showed significantly increased levels of HNE (0.412 +/- 0.023 nmol/ml) compared with normal healthy controls (0.205 +/- 0.018 nmol/ml).

Adult↗
PubMed1994

Oxidative damage to plasma proteins in adult respiratory distress syndrome.

There is evidence that patients with adult respiratory distress syndrome are under severe oxidative stress that leads to molecular damage. Oxidative stress appears to be inherent in the disease process as well as an unfortunate complication of essential treatment with oxygen. Eight critically ill patients with an established diagnosis of adult respiratory distress syndrome requiring high inspired oxygen concentrations administered by ultra high frequency jet ventilation, were studied. Three patients survived (38%). For the group as a whole, there was evidence of increased protein damage, measured on serial plasma samples as an increase in protein carbonyls (mean +/- SEM, 1.41 +/- 0.09 nmol/mg protein), compared with Intensive Care Unit (ICU) controls (1.24 +/- 0.09 nmol/mg protein), and normal healthy controls (0.940 +/- 0.04 nmol/mg protein). Protein thiol groups were decreased in the ARDS group (4.56 +/- 0.50 nmol/mg protein) compared with ICU controls (5.5 +/- 0.27 nmol/mg protein), and the normal healthy controls (6.55 +/- 0.52 nmol/mg protein). However, when ARDS patients were grouped as survivors and non-survivors, total plasma protein levels were lower in survivors (53.9 +/- 2.15 mg/ml) compared with non-survivors (78.2 +/- 4.68 mg/ml); but the protein thiol content was significantly higher (p = < 0.001) in survivors (6.24 +/- 0.09 nmol/mg protein) compared with non-survivors (3.56 +/- 0.16 nmol/mg protein). Serial plasma measurements of protein damage indicated two different patterns. Survivors had higher total plasma thiol values (protein corrected), which increased as the lung injury resolved, and failing protein carbonyl values. By contrast, non-survivors had low and failing protein thiols often accompanying rising carbonyls.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Proteins↗
PubMed1994

Linoleic acid and protein thiol changes suggestive of oxidative damage in the plasma of patients with adult respiratory distress syndrome.

Patients with the acute lung injury syndrome ARDS are under oxidative stress from the disease and from treatment with high inspired oxygen concentrations. Oxidative stress can lead to molecular damage by a variety of reactive oxygen intermediates generated in the lung. In the present study we sequentially monitor changes in plasma total lipid linoleic acid fatty acid levels, using GC-MS, and express these as a function of changes in plasma protein thiol values. In nine out of eleven ARDS patients there was a relationship between loss of protein thiols and loss of total lipid linoleic acid. In three patients changes in protein thiols preceded changes in total lipid linoleic acid by several days. Parallel decreases in plasma total lipid fatty acid esters of linoleic acid and protein thiols are suggestive of oxidative stress leading to molecular damage.

Blood Proteins↗
PubMed1994

Plasma 4-hydroxy-2-nonenal levels during cardiopulmonary bypass, and their relationship to the iron-loading of transferrin.

4-Hydroxy-2-nonenal (HNE) an aldehydic peroxidation produce of n-6 fatty acids, is formed predominantly in model systems when redox active transition metal ions, particularly iron, are present. During cardiopulmonary bypass surgery blood is circulated and oxygenated extracorporeally, and periods of tissue ischaemia-reoxygenation are introduced. Both events cause oxidative stress with the generation of reactive forms of oxygen leading to lipid peroxidation. During bypass iron is released often saturating plasma transferrin, and resulting in the appearance of chelatable iron in the plasma. Because such forms of iron can promote HNE formation in vitro, we have studied 12 bypass patients, 5 of whom had plasma iron-overload. Our results show a greater percentage increase in HNE formation during bypass when the plasma transferrin is iron-overloaded compared with matched controls not showing iron-overload.

Adult↗
PubMed1994

Antioxidants, nutritional supplements and life-threatening diseases.

Antioxidants are a complex and diverse group of molecules that protect key biological sites from oxidative damage. They usually act by removing or inactivating chemical intermediates that produce the ultimate oxidant. Different sites in the body have evolved to use highly specialised strategies to deal with free radicals and other reactive oxygen intermediates. Recent epidemiological evidence suggests that the development of life-threatening disease, such as cancer and heart disease, is linked to our dietary intake of micronutrients including antioxidants. Modification of dietary habits together with supplementation may provide a simple yet profound way to reduce deaths from these two major diseases. Sound scientific evidence to support a curative role for antioxidants in life-threatening diseases, however, is lacking.

Antioxidants↗
PubMed1994

Primary plasma antioxidants in adult respiratory distress syndrome patients: changes in iron-oxidizing, iron-binding, and free radical-scavenging proteins.

Ten adult patients (three male, age range, 15 to 67 years) with established ARDS were studied for serial changes in the proteinaceous antioxidant activities of their plasma. All had LISs in excess of 2.5 on admission to the study. Blood samples were taken as soon as possible after the diagnosis of ARDS, and from 10 patients at risk of developing ARDS. These were compared with healthy control subjects. Deoxyribose, phospholipids, and DNA were used as markers of damage in reactions generating inorganic and organic oxygen radicals and an oxo-iron species. The ability of plasma to inhibit such damage was expressed as antioxidant activity. This study does not address the clinical problem of why certain "at risk" patients develop ARDS, but rather the question of why some patients with established ARDS are better able than others to survive the disease. ARDS patients had transferrin levels that were significantly lower (1.76 +/- 0.13 gm/L) than those of normal controls (2.91 +/- 0.12 gm/L, p < 0.001), which decreased the ability of their plasma to protect phospholipid membranes and DNA against iron-stimulated free radical damage. The iron-oxidizing antioxidant properties of plasma were mainly dependent on the protein ceruloplasmin, concentrations of which were significantly higher in ARDS patients (0.387 +/- 0.04 gm/L) than in healthy controls (0.265 +/- 0.03 gm/L, p = < 0.05) or patients at risk of ARDS (0.24 +/- 0.04 gm/L, p = < 0.05). The iron-oxidizing (ferroxidase) antioxidant activities of plasma from ARDS patients, however, were similar to those of both control groups. Measurement of plasma ferroxidase activities confirmed that although more ceruloplasmin was present in the plasma of ARDS patients, enzyme activities were comparable to those of both control groups, which was suggestive of a loss of ceruloplasmin ferroxidase activity. Scavenging and radical-stimulating properties of plasma (devoid of iron-binding and iron-oxidizing properties) was partly dependent on protein thiol groups, which were lower in ARDS patients and in patients at risk of developing ARDS. Serial sample analysis revealed that ARDS patients showed substantial daily variations in biochemical parameters, implying that single time-point sampling may be unsuitable when studying these patients.

Adolescent↗
PubMed1993

Chelatable iron and copper can be released from extracorporeally circulated blood during cardiopulmonary bypass.

During cardiopulmonary bypass surgery blood is extracorporeally oxygenated and circulated before returning to the systemic arterial circulation. Blood undergoing extracorporeal dilution and circulation is exposed to non-physiological surfaces, which cause the activation of several regulatory cascades. Cells are also subjected to damaging shear stresses. Under such conditions neutrophils can be 'activated' to release reactive oxygen intermediates such as O2- and H2O2, and other cells can release proteolytic enzymes and metalloproteins. Collectively, these events can result in the release of micromolar quantities of redox active iron and copper. Bleomycin-detectable iron and phenanthroline-detectable copper were found in two out of four mock bypass experiments. However, there was no correlation between the presence of chelatable iron and copper and the activation of neutrophils measured as elastase.

Bleomycin↗