Biomedical subjects

Gerhard Spiteller

Publications and source records attributed to Gerhard Spiteller.

8 recordsLinked to original sources

PubMed2006

Peroxyl radicals: inductors of neurodegenerative and other inflammatory diseases. Their origin and how they transform cholesterol, phospholipids, plasmalogens, polyunsaturated fatty acids, sugars, and proteins into deleterious products.

The most oxygen-sensitive constituents of cells are polyunsaturated fatty acids (PUFAs), which are incorporated in the outermost layer of cells in the form of phospholipids. PUFAs easily suffer oxidation. Identical marker compounds of these lipid peroxidation (LPO) processes are generated in both neurodegenerative and cardiovascular diseases, indicating a close relationship between the inducers of these events. Apparently, any alteration of the cell membrane structure influences the channels crossing the cell wall and causes an influx of Ca2+ ions. Ca2+ ions induce activation of phospholipases, which cleave phospholipids. Thus, the generated free PUFAs serve as substrates of lipoxygenases (LOXs) and cyclooxygenases. LOXs transform PUFAs into lipid hydroperoxides (LOOHs). If an outside impact exceeds a certain limit, the catalyzing bivalent iron ions in LOXs are liberated. They cleave the enzymatically generated LOOH molecules and induce a switch to nonenzymatic LPO reactions that produce peroxyl radicals (LOO*). Although LOO* radicals are also intermediates in enzymatic LPO processes, they are prevented from leaving the enzyme complex before the reaction is completed by generation of LOOH molecules. LOO* radicals are much more reactive than LOOH molecules and attack nearly all types of biological molecules. The generated products seem to serve as ligands for proteins that in turn induce gene activation. Thus, PUFA-phospholipids are apparently the precursor molecules of signal molecules that respond in a dose-related manner to any event that influences the cell structure by inducing an appropriate gene response. In this paper an overview of the deleterious chemical reactions initiated by LOO* radicals is presented. Many of these reactions have not been taken into account in previous research. These include epoxidation of cholesterol-PUFA esters, plasmalogens, and sphingolipids, as well as the release of hydrogen peroxide by the reaction of LOO* radicals with alcohols (sugars) and amines. The oxidation of proteins generating plaque formation involves only the LOO* radical-sensitive functional groups in side chains of the protein backbone and is therefore a rather late event in the development of Alzheimer disease and atherosclerosis.

Carbohydrate Metabolism↗

PubMed2005

The relation of lipid peroxidation processes with atherogenesis: a new theory on atherogenesis.

The extremely high sensitivity of polyunsaturated fatty acids (PUFAs) to oxygen is apparently used by nature to induce stepwise appropriate cell responses. It is hypothesized that any alteration in the cell membrane structure induces influx of Ca2+ ions. Ca2+ ions are required to activate degrading enzymes, such as phospholipases and lipoxygenases (LOX) that transform PUFAs bound to membrane phospholipids to lipidhydroperoxides (LOOHs). Enzymatic reduction products of LOOHs seem to serve as ligands of proteins, which induce gene activation to initiate a physiological response. Increasing external impact on cells is connected with deactivation of LOX, liberation of the iron ion in its active center followed by cleavage of LOOH molecules to LO * radicals. LO * radicals induce a second set of responses leading to generation of unsaturated aldehydic phospholipids and unsaturated epoxyhydroxy acids that contribute to induction of apoptosis. Finally peroxyl radicals are generated by attack of LO * radicals on phospholipids. The latter attack nearly all types of cell constituents: Amino- and hydroxyl groups are oxidized to carbonyl functions, sugars and proteins are cleaved, molecules containing double bonds such as unsaturated fatty acids or cholesterol suffer epoxidation. LOOH molecules and iron ions at the cell wall of an injured cell are in tight contact with phospholipids of neighboring cells and transfer to these reactive radicals. Thus, the damaging processes proceed and cause finally necrosis except the chain reaction is stopped by scavengers, such as glutathione. Consequently, PUFAs incorporated into phospholipids of the cell wall are apparently equally important for the fate of a single organism as the DNA in the nucleus for conservation of the species. This review intends to demonstrate the connection of cell alteration reactions with induction of lipid peroxidation (LPO) processes and their relation to inflammatory diseases, especially atherosclerosis and a possible involvement of food. Previously it was deduced that food rich in cholesterol and saturated fatty acids is atherogenic, while food rich in n-3 PUFAs was recognized to be protective against vascular diseases. These deductions are in contradiction to the fact that saturated fatty acids withstand oxidation while n-3 PUFAs are subjected to LPO like all other PUFAs. Considering the influence of minor food constituents a new theory about atherogenesis and the influence of n-3 PUFAs is represented that might resolve the contradictory results of feeding experiments and chemical experiences. Cholesterol-PUFA esters are minor constituents of mammalian derived food, but main components of low density lipoprotein (LDL). The PUFA part of these esters occasionally suffers oxidation by heating or storage of mammalian derived food. There are indications that these oxidized cholesterol esters are directly incorporated into lipoproteins and transferred via the LDL into endothelial cells where they induce damage and start the sequence of events outlined above. The deduction that consumption of n-3 PUFAs protects against vascular diseases is based on the observation that people living on a fish diet have a low incidence to be affected by vascular diseases. Fish are rich in n-3 PUFAs; thus, it was deduced that the protective properties of a fish diet are due to n-3 PUFAs. Fish, fish oils, and vegetables contain besides n-3 PUFAs as minor constituents furan fatty acids (F-acids). These are radical scavengers and are incorporated after consumption of these nutrients into human phospholipids, leading to the assumption that not n-3 PUFAs, but F-acids are responsible for the beneficial efficiency of a fish diet.

Animals↗

PubMed2005

Furan fatty acids: occurrence, synthesis, and reactions. Are furan fatty acids responsible for the cardioprotective effects of a fish diet?

Furan FA (F-acids) are tri- or tetrasubstituted furan derivatives characterized by either a propyl or pentyl side chain in one of the alpha-positions; the other is substituted by a straight long-chain saturated acid with a carboxylic group at its end. F-acids are generated in large amounts in algae, but they are also produced by plants and microorganisms. Fish and other marine organisms as well as mammals consume F-acids in their food and incorporate them into phospholipids and cholesterol esters. F-acids are catabolized to dibasic urofuran acids, which are excreted in the urine. The biogenetic precursor of the most abundant F-acid, F6, is linoleic acid. Methyl groups in the beta-position are derived from adenosylmethionine. Owing to the different alkyl substituents, synthesis of F-acids requires multistep reactions. F-acids react readily with peroxyl radicals to generate dioxoenes. The radical-scavenging ability of F-acids may contribute to the protective properties of fish and fish oil diets against mortality from heart disease.

Cardiotonic Agents↗

PubMed2005

Is atherosclerosis a multifactorial disease or is it induced by a sequence of lipid peroxidation reactions?

The delivery of not only free cholesterol but also cholesterol esters to cells by low-density lipoprotein (LDL) has hitherto been unstudied. Minor compounds present in mammalian-derived food include cholesterol linoleate and arachidonate. Evidence is presented that these esters are directly incorporated into VLDL and are responsible for the deleterious effects of atherosclerosis. Cholesterol esterified with these polyunsaturated fatty acids (PUFAs) is readily oxidized at the PUFA residue during storage and heating. Apparently, the liver is unable to distinguish between nonoxidized and oxidized cholesterol PUFA esters and also incorporates the latter into VLDL, which is transformed to LDL. When this LDL is transferred to endothelial cells, the toxic products are liberated and induce cell damage. Cell damage is combined with structural changes that influence neighboring cells and cause an influx of Ca2+ ions and activation of phospholipases and lipoxygenases, resulting in production of lipid hydroperoxides (LOOHs). When the level of free PUFAs generated by phospholipases exceeds a certain limit, lipoxygenases commit suicide, causing liberation of iron ions. The latter react with LOOHs and thus induce a switch from enzymatic to nonenzymatic generation of lipid peroxidation (LPO) products. Although the LOO. radicals produced in enzymatic reactions are deactivated within the enzyme complex, LOO. radicals generated in nonenzymatic reactions are able to attack any biological compound, inducing severe damage. Apparently, iron ions and LOOH molecules at the surface of injured cells transfer the nonenzymatic LPO reactions to the phospholipid layer of bypassing lipoproteins, thus explaining why inflammatory diseases, such as diabetes, are combined with atherogenesis.

Aging↗

PubMed2004

Evaluation of factors to decrease bioavailability of cyclosporin A in rats with gentamicin-induced acute renal failure.

Focusing on the disposition of cyclosporin A (CsA) in the liver and intestine, effects of gentamicin-induced acute renal failure (ARF) on the decreased oral bioavailability of CsA were evaluated in rats. The area under the CsA concentration-time curve (AUC) in ARF rats after oral administration (5 mg/kg) significantly decreased by 43% as compared to the control, while the apparent oral clearance significantly increased by 76% of the control. The portal AUC of CsA in ARF rats with bile flow decreased by 67% as compared to the control rats. Without bile flow, the portal AUC of CsA in control rats decreased by 50% as compared to those with bile flow, whereas ARF rats without bile flow showed no notable change as compared to those with bile flow. The AUC of CsA mono-oxidative metabolite via CYP3A (M-OH) in ARF rats after oral or intravenous administration increased significantly by 84% or 241%, respectively, while there was no difference in the portal M-OH between control and ARF rats, suggesting that the elimination of M-OH was prolonged because of nephrotoxicity. Although the exsorption clearance of CsA from the blood circulation to the intestine after intravenous administration to ARF rats decreased significantly as compared to the control; and basolateral-to-apical transport of CsA through Caco-2 monolayers was significantly retarded in the presence of uremic toxins, there was no significant change in the total body clearance of CsA between ARF and control rats. Moreover, there were no effects of uremic toxins on the protein binding of CsA in plasma. These observations suggest that hepatic or intestinal CYP3A and P-glycoproteine (P-gp) are not likely to be concerned with lowering the oral bioavailability of CsA, and that bile function under the ARF condition induced by gentamicin is responsible for a marked decrease in the fraction absorbed of CsA in the small intestine.

Acute Kidney Injury↗

PubMed2003

Are lipid peroxidation processes induced by changes in the cell wall structure and how are these processes connected with diseases?

Apparently nature uses the unique sensitivity of polyunsaturated fatty acids (PUFAs) versus oxygen to generate chemical signals if the surface of a cell is influenced by an outside or inside event; for instance the attack of microorganisms, proliferation, aging or by treatment of isolated cells with surfactants. It seems that mammalian and plant cells respond equally to such changes in their structures by transformation of polyunsaturated fatty acids localized in the phospholipid layer of the cell wall to lipidhydroperoxides (LOOHs). These lipid peroxidation (LPO) processes involve all PUFAs, not only arachidonic acid.Slight physiological changes of the cell wall for instance by proliferation seem to activate enzymes, e.g., phospholipases and lipoxygenases (LOX). When an outside impact (for instance by attack of microorganisms) exceeds a certain level LOX commit suicide and liberate iron ions. These start a nonenzymatic LPO. Enzymatic and nonenzymatic LPO distinguish fundamentally which has not been recognized in the past. In the enzymatic LPO processes peroxyl radicals generated as intermediates cannot leave the enzyme complex. In contrast in a nonenzymatic LPO process peroxyl radicals are not trapped. They attack nearly any kind of biological molecules, for instance proteins. Thus only the amount of an outside impact decides if proliferation, apoptosis, or necrosis is started. Some evidence indicates that cancer might be the consequence of a low response of cells to induce apoptotic LPO processes. In contrast to high level of LPO processes induces diseases combined with inflammation, for instance rheumatic arthritis. After consumption of food rich in linoleic acid its LPO products become increased in low density lipoprotein (LDL). This LDL is able to enter endothelial cells and damage cells from inside, long before an inflammatory response is detectable.

Animals↗

PubMed2002

Are changes of the cell membrane structure causally involved in the aging process?

Lipid peroxidation is recognized by proliferation, wounding, and aging. The connecting link between these different events is a change in cell wall structure, which activates membrane bound phospholipases. These cleave phospholipids. Thus liberated polyunsaturated fatty acids (PUFAs) are substrates for lipoxygenases, which accept equally well linoleic acid and arachidonic acid and generate lipid hydroperoxides (LOOHs). If the amount of free PUFAs exceeds a certain amount, lipoxygenases commit suicide. The consequence is liberation of free iron ions that react with LOOHs by formation of radicals. These start a chain reaction. LOO* radicals produced in the course of this process attack proteins, nucleic acids, and also double bonds of all unsaturated compounds by epoxidation. Morever LOOHs are decomposed to toxic epoxy acids and alphabetagammadelta-unsaturated aldehydes. Both species react with glutathione. The resulting products seem to induce apoptosis. Since the products generated by wounding or aging are formed by decomposition of LOOHs the investigation of the aging processes can be simplified by studying the physiological action of artificially generated lipid peroxidation products derived from pure PUFAs. Degradation products of LOOHs are generated by thermal decomposition of fat-containing PUFAs. These products are induced into the body by adsorption in the intestine. They are at least partly incorporated in low density lipoproteins (LDLs). Primarily investigations seem to indicate that an overload of a diet rich in PUFAs induces only after two days an increase in oxidized LDL/PUFAs for a factor up to two in young people and for a factor of more than two in old individuals.

Aging↗

PubMedDate not supplied

Determination of hydroxyoctadecadienoic acids.

Oxidation of low-density lipoproteins (LDL) plays a crucial role in inflammatorydiseases and aging. The main oxidation products of LDL are stereoisomeric 9-hydroxy-10,12-octadecadienoic acids (9-HODEs) and 13-hydroxy-9,11-octadecadienoic acids (13-HODEs). Nevertheless the content of HODEs in natural oxidized LDL is low compared to other components, thus determination of HODEs requires a sample enrichment in most cases. Big losses are encountered during the necessary processing due to the instability of HODEs against acidic conditions. Therefore the use of labeled standards is required. Standards with an 18O label in the carboxylic group used previously may partly suffer a loss of the label by exchange with water. In this paper we describe an improved work-up procedure and the preparation of standards labeled with 18O in the hydroxylic group which is not exchangeable.

Aging↗