Plasma thiols, cognitive function and ageing.
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Aged↗
Biomedical subjects
D F Horrobin
Publications and source records attributed to D F Horrobin.
Exogenous gamma-linolenic acid alters hormone stimulated cyclic AMP levels in U937 cells.
Polyunsaturated fatty acids are selectively cytotoxic in culture. Incorporation of these fatty acids leads to profound changes in membrane fatty acid composition which in turn may alter the activity of transmembrane receptor/effector systems. In U937 cells, hormone stimulated production of cyclic AMP can be reduced by 30% following incubation with gamma-linolenic acid (18:3n-6). It is suggested that beta-adrenoreceptor number, subtype and adenylyl cyclase stimulation may be regulated by alterations in membrane fatty acid composition as a result of changes in the levels of polyunsaturated fatty acids and alterations in eicosanoid production.
Adrenergic beta-Agonists↗
High levels of polyunsaturated fat may inhibit cancer growth.
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Fats, Unsaturated↗
Comparison of the grignard deacylation TLC and HPLC methods and high resolution 13C-NMR for the sn-2 positional analysis of triacylglycerols containing gamma-linolenic acid.
There is increasing evidence that the fatty acid, gamma-linolenic acid (GLA) is the effective component found in evening primrose oil (EPO) which has been shown to bring about clinical improvement in a number of disease conditions. The two major triacylglycerols (TAGs) in EPO are trilinolein (LLL) and a TAG species containing one GLA and two linoleic (LA) fatty acid chains. This latter TAG, called dilinoleoyl-mono-gamma-linolenin (DLMG or Oenotheral), makes up about 15% by weight of EPO and accounts for over one-half of the total amount of GLA present in EPO. Although DLMG is comprised of three possible isomers, the abbreviation is used to represent the naturally occurring mixture of these isomers. We have isolated DLMG from EPO and also prepared its three possible isomers, sn-GLL, sn-LGL and sn-LLG, and carried out the sn-2 positional analysis using three different approaches, namely, Grignard deacylation TLC and HPLC methods and high resolution 13C-NMR spectroscopy. The results of the sn-2 positional analysis for both the natural and synthetic TAGs containing LA and GLA in this study using the three approaches are all in very good agreement. This indicates that the three positional analysis methods are valid within their acceptable error margin and can be used with confidence in determining the fatty acid composition of the sn-2 position. Given the increased availability of NMR spectrometers this method might prove to be the easiest and most convenient in determining the sn-2 position for oil or TAG samples that contain a small number of different fatty acids providing all the 13C-NMR carbonyl resonances are well resolved.
Anti-Inflammatory Agents↗
Vitamin E blocks the cytotoxic effect of gamma-linolenic acid when administered as late as the time of onset of cell death--insight into the mechanism of fatty acid induced cytotoxicity.
Certain polyunsaturated fatty acids can selectively kill tumor cell lines while causing little to no harm to normal cell lines. However, the mechanism of this cytotoxicity is only partially understood. Antioxidants such as vitamin E have been shown to be capable of completely blocking the cytotoxic response when administered concomitantly with the fatty acid. We report here that when vitamin E was added as late as 6 days following fatty acid treatment, at a time point when the process of cell death was well underway, any further development of cell death was blocked. This implies that the mechanism of fatty acid induced cytotoxicity does not involve a gradual compromising of the cell over the 5-7 day time course of cell death. Instead, the event triggering cell death is an oxidative phenomenon occurring over a short time span of minutes or hours, not days, and is completely blocked by vitamin E.
Antioxidants↗
Inhibition of neutrophil respiratory burst and cytokine priming by gamma-linolenic acid.
The effect of n-6 fatty acids, particularly gamma-linolenic acid (GLA), on the oxidase response and neutrophil priming by tumour necrosis factor alpha and interleukin 8 was studied in both normal volunteers and patients with obstructive jaundice. GLA inhibited the neutrophil respiratory burst at concentrations higher than 50 mummol/l, but abolished cytokine priming at concentrations as low as 1 mummol/l. Inhibition was not the result of either cytotoxicity to the neutrophils or alteration in cytosolic free calcium homoeostasis. It is concluded that GLA is a potential inhibitor of neutrophil priming by cytokines and of the oxidative response.
Aged↗
Ascorbic acid and prostaglandin synthesis.
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Animals↗
Schizophrenia as a membrane lipid disorder which is expressed throughout the body.
Clinical, biochemical and genetic evidence now indicates that schizophrenia is a disorder of membrane phospholipid metabolism associated with increased loss of highly polyunsaturated fatty acids from membranes owing to enhanced activity of a phospholipase A2. This changes the properties of membranes throughout the body and is responsible for such physical abnormalities as reduced vasodilator responses to niacin and histamine and altered immunological functions. A modest membrane abnormality is likely to produce its most serious consequences in the brain, which requires the co-ordinated sequential and parallel activities of millions of neurons. The concept leads to testable proposals for relatively simple and safe treatment modalities.
Arachidonic Acid↗
Membrane fatty acids, niacin flushing and clinical parameters.
Clinical definitions of schizophrenia are unreliable and difficult to use. The niacin flush test, which involves prostaglandin-induced vasodilatation, offers a method of exploring essential fatty acid metabolism in schizophrenic patients and may serve to define a subgroup of patients. In a multicentre study of schizophrenic patients with negative symptoms, we have examined the clinical accompaniments of the niacin response. Patients failing to flush with niacin showed significantly reduced levels of arachidonic and docosahexaenoic acids. Conversion from non-flushing to flushing during the 6 month supplementation period was predicted by an increase in arachidonic acid levels in red blood cell membranes irrespective of nature of supplementation. In this study, patients were selected for their negative symptoms and, therefore, it was not surprising that further measures of negative or positive symptoms did not predict flushing. However, an increased score for affective symptoms was significantly associated with a positive flush response. The stability of the niacin test needs to be examined in relation to the periodicity of symptoms in schizophrenia and manic depressive illness. New information on the anandamide system suggests that it may be associated with periodic phenomena and should be investigated in relation to the niacin test.
Adult↗
Essential fatty acids and abnormal involuntary movements in the general male population: a study of men born in 1933.
Spontaneous and tardive dyskinesias were studied in a random population sample of 446 men, aged 59 years. Dyskinesia, defined as an AIMS score of at least 2 in any body part, was seen in 15.1% (n = 74). Dyskinetic men had a higher cigarette consumption, and they had higher frequencies of psychiatric morbidity and exposure to neuroleptics. Dyskinesia was also associated with several abnormalities in EFA concentrations in plasma, but the most consistent finding was the low arachidonic acid levels in phospholipids, triglycerides and cholesterol esters. In a logistic regression model, cigarette consumption (P < 0.02), exposure to neuroleptics (P < 0.01), and low arachidonic acid levels in the phospholipid fraction (P < 0.0001) were independently associated with dyskinesia.
Antipsychotic Agents↗
Phospholipases: in search of a genetic base of schizophrenia.
Evidence from a variety of clinical and biochemical sources indicates alterations in phospholipid synthesis and activity in schizophrenia. We review a recent study which suggests that a genetic variant near the promotor region of the gene for cytosolic phospholipase A2, the rate-limiting enzyme in the synthesis of prostaglandins from arachidonic acid (AA), is associated with schizophrenia. These findings are consistent with a extensive body of literature which suggests alterations in membrane phospholipids in schizophrenia.
Alleles↗
Essential fatty acid metabolism in cultured rat cardiomyocytes in response to either N-6 or N-3 fatty acid supplementation.
In this study we demonstrate that cultured rat cardiomyocytes possess the capacity to desaturate/elongate essential fatty acids (EFAs). Alpha-linolenic acid (ALA) conversion to higher metabolites was greater than linoleic acid (LA) conversion, according to the higher affinity of the delta-6-desaturase enzyme for the n-3 than for the n-6 EFAs. Gamma-linolenic acid (GLA) supplementation to the culture medium had no influence on LA conversion; but the addition of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids significantly decreased the formation of interconversion products from LA. The conversion of ALA to higher metabolites was greatly affected by GLA; EPA had no effect on ALA conversion, while DHA significantly inhibited it. Both GLA (converted mostly to dihomo-gamma-linolenic acid) and EPA can be removed from phospholipids and addressed to prostanoid biosynthesis, so avoiding their potential accumulation and the inhibition of their own production. Our data clearly indicate that supplementation of the culture medium with either n-6 or n-3 fatty acids can cause reduced levels of the other series of fatty acids. This effect may be undesirable, since both n-6 and n-3 fatty acids are important in the prevention of coronary diseases.
Animals↗
Regulation of the expression of E-cadherin on human cancer cells by gamma-linolenic acid (GLA).
E-cadherin is a cell to cell adhesion molecule which acts as a suppressor of metastasis. This study examined the effect of gamma-linolenic acid (GLA), a n-6 polyunsaturated fatty acid, on the expression of E-cadherin in human cancer cells. Western blotting studies demonstrated that treatment of cells with GLA for 24 h increased the expression of E-cadherin in lung, colon, breast, melanoma, and liver cancer cells, but not in endothelial cells and fibroblasts. The results were confirmed by immunocytochemistry. In contrast, two other n-6 fatty acids, linoleic acid and arachidonic acid, failed to induce these changes. The increased expression of E-cadherin was correlated with reduced in vitro invasion and increased aggregation, indicating that the increased E-cadherin expression induced by GLA was biologically active. These data add GLA to the short list of E-cadherin up-regulatory factors. The up-regulation of E-cadherin expression in human cancer cells may contribute to the anticancer properties of GLA.
Antineoplastic Agents↗
Ethical imperative to publish extends to academics too.
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Drug Industry↗
Evening primrose oil and atopic eczema.
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Dermatologic Agents↗
DNA-protein and membrane-lipid: competing paradigms in biomedical research.
Most current biomedical science research is based on the idea that DNA and the RNA and proteins whose structures are specified by DNA are of overwhelming importance in human disease. While they are undoubtedly of major significance, their practical importance may have been exaggerated. Lipids which make up the bulk of cell and other membranes, and which modulate the behaviour of most proteins may be of at least equal importance. Moreover, lipids offer more opportunities for practical therapeutic intervention.
DNA↗
Possible relevance of phospholipid abnormalities and genetic interactions in psychiatric disorders: the relationship between dyslexia and schizophrenia.
The fatty acids of cell membrane phospholipids are essential for normal membrane structures, for the functioning of membrane-bound and membrane-associated proteins and for normal cell-signalling responses. In dyslexia, there is evidence for reduced incorporation of docosahexaenoic acid and arachidonic acid into cell membranes, while in schizophrenia, there is evidence for an increased rate of docosahexaenoic acid and arachidonic acid loss from membranes because of enhanced phospholipase A2 activity. The presence of both defects will cause a much greater degree of abnormality than either one alone. It is hypothesized that unequivocal clinical schizophrenia may occur when both genes are present in the same individual. The dyslexia gene along will produce dyslexia while the schizophrenia gene alone may produce bipolar or schizoaffective disorders. These proposals could explain: 1. The reduced asymmetry of the brain, especially of the planum temporale in both schizophrenia and dyslexia; 2. The schizotypal personality characteristics of dyslexics; 3. The increased risks of dyslexia in families with a schizophrenic proband; 4. The increased risks of bipolar and schizoaffective disorders in families with a schizophrenic proband; 5. The earlier onset and possibly increased severity of both disorders in males since females have a lower requirement for arachidonic acid and docosahexaenoic acid; 6. The absence of selective pressure against schizophrenia since reproduction would be impaired only when the schizophrenic gene coexisted with a dyslexic gene. The schizophrenic gene alone might even lead to improved reproductive performance.
Arachidonic Acid↗
Abnormal membrane concentrations of 20 and 22-carbon essential fatty acids: a common link between risk factors and coronary and peripheral vascular disease?
Although elevated levels of cholesterol are associated with increased risks of coronary and peripheral vascular disease, the association frequently fails to provide a causative explanation at the individual level. New hypotheses are required which, whether or not they are correct, will provide new lines of research. It is proposed here that the causes of vascular disease are abnormal membrane phospholipid concentrations of the 20-carbon and 22-carbon essential fatty acids (EFAs) of the n-6 and n-3 series. These levels become abnormal with ageing, with stress and in response to smoking, high cholesterol levels and high saturated fat intakes. They are also abnormal in patients with diabetes and hypertension. The effects of these EFAs and their metabolites include lowering of triglycerides, elevation of high-density lipoprotein (HDL)-cholesterol, reduction of blood pressure, vasodilatation, reduction of fibrinogen levels and inhibition of platelet aggregation and of cardiac arrhythmias. Prospective studies have shown that abnormal levels of these fatty acids are predictive of future coronary death. Controlled trials of treatment have demonstrated that provision of the fatty acids reduces both coronary and total mortality. Further experimental and clinical investigations of the roles of appropriate membrane concentrations of these fatty acids are justified.
Animals↗