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BBA - Biomembranes (v.1818, #10)

Editorial Board (pp. i).

Oxidized phospholipids—Their properties and interactions with proteins by Albin Hermetter; Paavo Kinnunen; Corinne Spickett (pp. 2373-2373).

Chemistry of phospholipid oxidation by Ana Reis; Corinne M. Spickett (pp. 2374-2387).

The oxidation of lipids has long been a topic of interest in biological and food sciences, and the fundamental principles of non-enzymatic free radical attack on phospholipids are well established, although questions about detail of the mechanisms remain. The number of end products that are formed following the initiation of phospholipid peroxidation is large, and is continually growing as new structures of oxidized phospholipids are elucidated. Common products are phospholipids with esterified isoprostane-like structures and chain-shortened products containing hydroxy, carbonyl or carboxylic acid groups; the carbonyl-containing compounds are reactive and readily form adducts with proteins and other biomolecules. Phospholipids can also be attacked by reactive nitrogen and chlorine species, further expanding the range of products to nitrated and chlorinated phospholipids. Key to understanding the mechanisms of oxidation is the development of advanced and sensitive technologies that enable structural elucidation. Tandem mass spectrometry has proved invaluable in this respect and is generally the method of choice for structural work. A number of studies have investigated whether individual oxidized phospholipid products occur in vivo, and mass spectrometry techniques have been instrumental in detecting a variety of oxidation products in biological samples such as atherosclerotic plaque material, brain tissue, intestinal tissue and plasma, although relatively few have achieved an absolute quantitative analysis. The levels of oxidized phospholipids in vivo is a critical question, as there is now substantial evidence that many of these compounds are bioactive and could contribute to pathology. The challenges for the future will be to adopt lipidomic approaches to map the profile of oxidized phospholipid formation in different biological conditions, and relate this to their effects in vivo. This article is part of a Special Issue entitled: Oxidized phospholipids—their properties and interactions with proteins.► The concepts of phospholipid oxidation by radicals and other oxidants are given. ► A wide variety of oxidized phospholipid structures are known. ► Recent advances and outstanding questions in the field are discussed. ► The application of mass spectrometry to oxPL analysis is described. ► Details are given of the concentrations of oxPL in biological and clinical samples.

Keywords: Lipid peroxidation; Radical oxidation; Mass spectrometry; Oxidative lipidomics; NMR; Inflammation

Biophysics of lipid bilayers containing oxidatively modified phospholipids: Insights from fluorescence and EPR experiments and from MD simulations by Piotr Jurkiewicz; Olzynska Agnieszka Olżyńska; Lukasz Cwiklik; Elena Conte; Pavel Jungwirth; Francesco M. Megli; Martin Hof (pp. 2388-2402).

This review focuses on the influence of oxidized phosphatidylcholines (oxPCs) on the biophysical properties of model membranes and is limited to fluorescence, EPR, and MD studies. OxPCs are divided into two classes: A) hydroxy- or hydroperoxy-dieonyl phospatidylcholines, B) phospatidylcholines with oxidized and truncated chains with either aldehyde or carboxylic group. It was shown that the presence of the investigated oxPCs in phospholipid model membranes may have the following consequences: 1) decrease of the lipid order, 2) lowering of phase transition temperatures, 3) lateral expansion and thinning of the bilayer, 4) alterations of bilayer hydration profiles, 5) increased lipid mobility, 6) augmented flip-flop, 7) influence on the lateral phase organisation, and 8) promotion of water defects and, under extreme conditions (i.e. high concentrations of class B oxPCs), disintegration of the bilayer. The effects of class A oxPCs appear to be more moderate than those observed or predicted for class B. Many of the abovementioned findings are related to the ability of the oxidized chains of certain oxPCs to reorient toward the water phase. Some of the effects appear to be moderated by the presence of cholesterol. Although those biophysical alternations are found at oxPC concentrations higher than the total oxPC concentrations found under physiological conditions, certain organelles may reach such elevated oxPC concentrations locally. It is a challenge for the future to correlate the biophysics of oxidized phospholipids to metabolic studies in order to define the significance of the findings presented herein for pathophysiology. This article is part of a Special Issue entitled: Oxidized phospholipids—their properties and interactions with proteins.► Effects of oxidation on the biophysics of model lipid membranes are reviewed. ► Well-defined oxidized PCs being studied using fluorescence, EPR, and MD are considered. ► Oxidized chains reorient toward water phase and change bilayer properties. ► Structure, phase transition, hydration, fluidity, and flip-flop can be affected.

Keywords: Oxidized phospholipids; Liposome; Fluorescence; EPR; Molecular dynamics

Esterified eicosanoids: Generation, characterization and function by Victoria J. Hammond; Valerie B. O'Donnell (pp. 2403-2412).

Eicosanoids are oxidation products of C20 polyunsaturated fatty acids (e.g. arachidonic acid) that include prostaglandins, thromboxanes, leukotrienes and hydroperoxy fatty acids. They have important biological roles in vivo, including regulation of renal, cardiovascular and gastrointestinal function. Historically, eicosanoids were thought to mediate their signaling actions exclusively as free acids, however evidence is now emerging that they may also be generated attached to other functional groups including phospholipids and glycerol, and that these more complex forms are pathophysiological signaling mediators in their own right. Early studies showed that exogenously added eicosanoids could become esterified into membrane phospholipids of cells, while more recently, it was uncovered that esterified eicosanoids are formed endogenously. This review summarizes our current knowledge of this area, starting with the early discoveries documenting what is known about eicosanoid generation and their esterification, and moving on to discuss the discovery that esterified eicosanoids are generated endogenously by a number of different cell types. Recent research that is highlighting new structures and functions of these important lipid mediators will be presented. This article is part of a Special Issue entitled: Oxidized phospholipids—their properties and interactions with proteins.► Description of esterified eicosanoids generated by innate immune cells. ► Formation of bioactive lipids by lipoxygenase and cyclooxygenases. ► Lipid signaling in inflammation.

Keywords: Phospholipid; Oxidation; Lipoxygenase; Cyclooxygenase; Mass spectrometry

Oxidized phospholipids as biomarkers of tissue and cell damage with a focus on cardiolipin by Alejandro K. Samhan-Arias; Jing Ji; Olga M. Demidova; Louis J. Sparvero; Weihong Feng; Vladimir Tyurin; Yulia Y. Tyurina; Michael W. Epperly; Anna A. Shvedova; Joel S. Greenberger; Bayir Hülya Bayır; Valerian E. Kagan; Andrew A. Amoscato (pp. 2413-2423).

Oxidized phospholipid species are important, biologically relevant, lipid signaling molecules that usually exist in low abundance in biological tissues. Along with their inherent stability issues, these oxidized lipids present themselves as a challenge in their detection and identification. Often times, oxidized lipid species can co-chromatograph with non-oxidized species making the detection of the former extremely difficult, even with the use of mass spectrometry. In this study, a normal-phase and reverse-phase two dimensional high performance liquid chromatography (HPLC)–mass spectrometric system was applied to separate oxidized phospholipids from their non-oxidized counterparts, allowing unambiguous detection in a total lipid extract. We have utilized bovine heart cardiolipin as well as commercially available tetralinoleoyl cardiolipin oxidized with cytochrome c (cyt c) and hydrogen peroxide as well as with lipoxygenase to test the separation power of the system. Our findings indicate that oxidized species of not only cardiolipin, but other phospholipid species, can be effectively separated from their non-oxidized counterparts in this two dimensional system. We utilized three types of biological tissues and oxidative insults, namely rotenone treatment of lymphocytes to induce mitochondrial damage and cell death, pulmonary inhalation exposure to single walled carbon nanotubes, as well as total body irradiation, in order to identify cardiolipin oxidation products, critical to the cell damage/cell death pathways in these tissues following cellular stress/injury. Our results indicate that selective cardiolipin (CL) oxidation is a result of a non-random free radical process. In addition, we assessed the ability of the system to identify CL oxidation products in the brain, a tissue known for its extreme complexity and diversity of CL species. The ability of the two dimensional HPLC–mass spectrometric system to detect and characterize oxidized lipid products will allow new studies to be formulated to probe the answers to biologically important questions with regard to oxidative lipidomics and cellular insult. This article is part of a Special Issue entitled: Oxidized phospholipids — their properties and interactions with proteins.► Oxidized lipids have been separated from non-oxidized lipids using a 2D HPLC–MS system. ► Oxidized CL species have been detected in four different tissue settings. ► Oxidation of CL is a non-random process. ► Similar oxidized CL species appear with different biological insults.

Keywords: Abbreviations; HPLC; high performance liquid chromatography; LC–MS; liquid chromatography–mass spectrometry; Q-TOF; quadrupole-time of flight; ADP; adenosine dinucleotide diphosphate; NDPK; nucleoside diphosphate kinase; CCI; control cortical impact; CL; cardiolipin; BHC; bovine heart cardiolipin; TLCL; 1,1′,2,2′-tetralinoleoylcardiolipin; PG; phosphatidylglycerol; PI; phosphatidylinositol; PE; phosphatidylethanolamine; PS; phosphatidylserine; PC; phosphatidylcholine; SM; sphinglomyelin; cyt; c; cytochrome c; DTPA; diethylenetriaminepentaacetic acid; H; ₂; O; ₂; hydrogen peroxide; HEPES; 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; PBS; phosphate buffered saline; TBI; traumatic brain injury; 1D; 1st dimension; 2D; 2nd dimension; ROS; reactive oxygen species; SWCNTs; single-walled carbon nanotubesLipids; Mass spectrometry; Oxidative lipidomics; Cardiolipin; Apoptosis; High performance liquid chromatography

Protein modification by oxidized phospholipids and hydrolytically released lipid electrophiles: Investigating cellular responses by Jody C. Ullery; Lawrence J. Marnett (pp. 2424-2435).

Oxygen is essential for the growth and function of mammalian cells. However, imbalances in oxygen or abnormalities in the ability of a cell to respond to oxygen levels can result in oxidative stress. Oxidative stress plays an important role in a number of diseases including atherosclerosis, rheumatoid arthritis, cancer, neurodegenerative diseases and asthma. When membrane lipids are exposed to high levels of oxygen or derived oxidants, they undergo lipid peroxidation to generate oxidized phospholipids (oxPL). Continual exposure to oxidants and decomposition of oxPL results in the formation of reactive electrophiles, such as 4-hydroxy-2-nonenal (HNE). Reactive lipid electrophiles have been shown to covalently modify DNA and proteins. Furthermore, exposure of cells to lipid electrophiles results in the activation of cytoprotective signaling pathways in order to promote cell survival and recovery from oxidant stress. However, if not properly managed by cellular detoxification mechanisms, the continual exposure of cells to electrophiles results in cytotoxicity. The following perspective will discuss the biological importance of lipid electrophile protein adducts including current strategies employed to identify and isolate protein adducts of lipid electrophiles as well as approaches to define cellular signaling mechanisms altered upon exposure to electrophiles. This article is part of a Special Issue entitled: Oxidized phospholipids—their properties and interactions with proteins.► Proteomic analysis of electrophile consequences on cells shows severe protein adduction ► Protein adduction leads to significant global gene expression changes, as observed by microarray ► It is important to adopt a biological approach to define effects of electrophiles on cell function

Keywords: Lipid electrophile; Click chemistry; Proteomics; Microarray; Cellular response to electrophile; Oxidized phospholipid

Protein modification by aldehydophospholipids and its functional consequences by Ute Stemmer; Albin Hermetter (pp. 2436-2445).

Phospholipid aldehydes represent a particular subclass of lipid oxidation products. They are chemically reactive and can form Schiff bases with proteins and aminophospholipids. As chemically bound molecular entities they modulate the functional properties of biomolecules in solution and the surface of supramolecular systems including plasma lipoproteins and cell membranes. The lipid–protein and lipid–lipid conjugates may be considered the active primary platforms that are responsible for the biological effects of aldehydophospholipids, e.g. receptor binding, cell signaling, and recognition by the immune system. Despite the fact that aldehydophospholipids are covalently associated, they are subject to exchange between nucleophiles since their imine conjugates are not stable. As a consequence, aldehydophospholipids exist in a dynamic equilibrium between different “states” depending on the lipid and protein environment. Aldehydophospholipids may also contribute to the systemic administration and activity of oxidized phospholipids by inducing release of microparticles by cells. These effects are lipid-specific. Future studies should help clarify the mechanisms and consequences of these membrane-associated effects of “phospholipid stress”. This article is part of a Special Issue entitled: Oxidized phospholipids—their properties and interactions with proteins.►The manuscript gives an overview of biophysical and biochemical properties of aldehydophospholipid–protein adducts. ►Aldehydophospholipids affect the physiological functions of atherogenic and antiatherogenic lipoproteins. ►Aldehydophospholipids target many cellular proteins apart from classical lipid and lipoprotein receptors. ►Aldehydophospholipid–protein adducts elicit autoimmune responses.

Keywords: Abbreviations; BSA; bovine serum albumin; BY; BODIPY™; HAEC; human aortic endothelial cells; HDL; high density lipoprotein; HNE; hydroxyl-nonenal; HOdiA-PC; 1-palmitoyl-2-(5-hydroxy-8-oxo-6-octenedioyl); sn; -glycero-3-phosphocholine; HOOA-PC; 1-palmitoyl-2-(5-hydroxy-8-oxooct-6-enoyl)-; sn; -glycero-3-phosphocholine; IL; interleukin; KDdiaPC; 1-palmitoyl-2-(9-keto-10-dodecendioyl)-; sn; -glycero-3-phosphocholine; KOdiA- PC; 1-palmitoyl-2-(5-keto-6-octene-dioyl)-; sn; -glycero-3-phosphocholine; KOOA-PC; 1-palmitoyl-(5-keto-8-oxo-6-octenoyl)-; sn; -glycero-3-phosphocholine; LDL; low density lipoprotein; MDA; malondialdehyde; oxLDL; oxidized low density lipoprotein; (ox)PAPC; (oxidized) 1-palmitoyl-2-arachidonoyl-; sn; -glycero-3-phosphocholine; oxPL; oxidized phospholipid; PAF; platelet activating factor; PazePC; 1-palmitoyl-2-azelaoyl-; sn; -glycero-3-phosphocholine; PC; phosphatidylcholine; PE; phosphatidylethanolamine; PGPC; 1-palmitoyl-2-glutaroyl-; sn; -glycero-3-phosphocholine; PLA; phospholipase A; PLPC; 1-palmitoyl-; sn; -glycero-3-phosphocholine; PONPC; 1-palmitoyl-2-(9-oxononanayl)-; sn; -glycero-3-phosphocholine; POVPC; 1-palmitoyl-2-(5-oxovaleroyl)-; sn; -glycero-3-phosphocholine; PoxnoPC; 1-palmitoyl-2-(9-oxo-nonanoyl)-; sn; -glycero-3-phosphocholine; PS; phosphatidylserine; PUFA; poly unsaturated fatty acid; ROS; reactive oxygen species; TLR; toll-like receptor; VSMC; vascular smooth muscle cellsOxidized phospholipids; Oxidized lipoproteins; Atherosclerosis; Lipoprotein–cell interaction; Lipid toxicity

Protein-oxidized phospholipid interactions in cellular signaling for cell death: From biophysics to clinical correlations by Paavo K.J. Kinnunen; Kai Kaarniranta; Ajay K. Mahalka (pp. 2446-2455).

Oxidative stress is associated with several major ailments. However, it is only recently that the developments in our molecular level understanding of the consequences of oxidative stress in modifying the chemical structures of biomolecules, lipids in particular, are beginning to open new emerging insights into the significance of oxidative stress in providing mechanistic insights into the etiologies of these diseases. In this brief review we will first discuss the role of lipid oxidation in controlling the membrane binding of cytochrome c, a key protein in the control of apoptosis. We then present an overview of the impact of oxidized phospholipids on the biophysical properties of lipid bilayers and continue to discuss, how these altered properties can account for the observed enhancement of formation of intermediate state oligomers by cytotoxic amyloid forming peptides associated with pathological conditions as well as host defense peptides of innate immunity. In the third part, we will discuss how the targeting of oxidized phospholipids by i) pathology associated peptides and ii) host defense peptides can readily explain the observed clinical correlations associating Alzheimer's and Parkinson's diseases with increased risk for type 2 diabetes and age-related macular degeneration, and the apparent protective effect of Alzheimer's and Parkinson's diseases from some cancers, as well as the inverse, apparent protection by cancer from Alzheimer's and Parkinson's diseases. This article is part of a Special Issue entitled: Oxidized phospholipids—Their properties and interactions with proteins.► The manuscript gives a concise overview of oxidized phospholipid biophysics. ► Biophysics of oxidized phospholipids explains the lipid binding of cytochrome c. ► Biophysics of oxidized lipids can explain enhanced amyloid fibril formation. ► We explain the correlations between neurodegenerative disorders, 2DM, and cancer.

Keywords: Abbreviations; A2E; N-retinylidene-N-retinylethanolamine; 2DM; type 2 diabetes; apo; apolipoprotein; Aβ; Alzheimer β-peptide; AD; Alzheimer's disease; AMD; age-related macular degeneration; AMP; antimicrobial peptides; CMC; critical micelle concentration; cyt c; cytochrome c; FAF; Finnish type familial amyloidosis; HDP; host defense proteins/peptides; IAPP; islet associated polypeptide; IDCP; intrinsically disordered cytotoxic peptides; LB; Lewy body; MPT; mitochondrial permeability transition; NBD; nitro-2,1,3-benzoxadiaz-ol-4-yl; oxCL; oxidized cardiolipin; oxPC; oxidized phosphatidylcholine; oxPL; oxidized phospholipids; oxPS; oxidized phosphatidylserine; oxtlCL; oxidized tetralinoleyl cardiolipin; PAfP; pathology associated amyloid forming proteins/peptides; PazePC; 1-palmitoyl-2-azelaoyl-; sn; -glycero-3-phosphocholine; PD; Parkinson's disease; PoxnoPC; 1-palmitoyl-2-(9′-oxo-nonanoyl)-; sn; -glycero-3-phosphocholine; PUFA; polyunsaturated fatty acyl; ROS; reactive oxygen species; RPE; retinal pigment epithelium; sn; stereochemical notation; syn; synuclein; tlCL; tetra-linoleoyl-cardiolipinOxidized phospholipid; Biomembrane; Protein aggregation; Misfolding; Amyloid

Bioactive oxidatively truncated phospholipids in inflammation and apoptosis: Formation, targets, and inactivation by Thomas M. McIntyre (pp. 2456-2464).

This report reviews structurally related phospholipid oxidation products that are biologically active where molecular mechanisms have been defined. Phospholipids containing polyunsaturated fatty acyl residues are chemically or enzymatically oxidized to phospholipid hydroperoxides, which may fragment on either side of the newly introduced peroxy function to form phospholipids with a truncated sn-2 residue. These truncated phospholipids not subject to biologic control of their production and, depending on the sn-2 residue length and structure, can stimulate the plasma membrane receptor for PAF. Alternatively, these chemically formed products can be internalized by a transport system to either stimulate the lipid activated nuclear transcription factor PPARγ or at higher levels interact with mitochondria to initiate the intrinsic apoptotic cascade. Intracellular PAF acetylhydrolases specifically hydrolyze truncated phospholipids, and not undamaged, biosynthetic phospholipids, to protect cells from oxidative death. Truncated phospholipids are also formed within cells where they couple cytokine stimulation to mitochondrial damage and apoptosis. The relevance of intracellular truncated phospholipids is shown by the complete protection from cytokine induced apoptosis by PAF acetylhydrolase expression. This protection shows truncated phospholipids are the actual effectors of cytokine mediated toxicity. This article is part of a Special Issue entitled: Oxidized phospholipids—their properties and interactions with proteins.► Phospholipid hydroperoxides fragment to truncated phospholipids. ► Truncated phospholipids activate the external PAF receptor, and after internalization activate PPARγ or depolarize mitochondria to initiate apoptosis. ► Cytokine signaling creates internal truncated phospholipids that are required mediators of cytokine-induced apoptosis. ► PAF acetylhydrolases specifically hydrolyze truncated phospholipids, protecting cells from oxidative death.

Keywords: Oxidized phospholipid; PAF; PAF acetylhydrolase; Inflammation

The innate immune response to products of phospholipid peroxidation by David Weismann; Christoph J. Binder (pp. 2465-2475).

Lipid peroxidation occurs in the context of many physiological processes but is greatly increased in various pathological situations. A consequence of phospholipid peroxidation is the generation of oxidation-specific epitopes, such as phosphocholine of oxidized phospholipids and malondialdehyde, which form neo-self determinants on dying cells and oxidized low-density lipoproteins. In this review we discuss evidence demonstrating that pattern recognition receptors of the innate immune system recognize oxidation-specific epitopes as endogenous damage-associated molecular patterns, allowing the host to identify dangerous biological waste. Oxidation-specific epitopes are important targets of both cellular and soluble pattern recognition receptors, including toll-like and scavenger receptors, C-reactive protein, complement factor H, and innate natural IgM antibodies. This recognition allows the innate immune system to mediate important physiological house keeping functions, for example by promoting the removal of dying cells and oxidized molecules. Once this system is malfunctional or overwhelmed the development of diseases, such as atherosclerosis and age-related macular degeneration is favored. Understanding the molecular components and mechanisms involved in this process, will help the identification of individuals with increased risk of developing chronic inflammation, and indicate novel points for therapeutic intervention. This article is part of a Special Issue entitled: Oxidized phospholipids—their properties and interactions with proteins.► Phospholipid peroxidation results in the formation of oxidation-specific epitopes. ► Oxidation-specific epitopes are recognized by soluble and cellular pattern recognition receptors. ► Recognition by these receptors promotes the clearance of biological waste. ► This innate defense is challenged by increased oxidative stress, such as in chronic inflammation.

Keywords: Abbreviations; 4-HNE; 4-hydroxynonenal; AMD; age-related macular degeneration; AGE(s); advanced glycation end product(s); ApoE; apolipoprotein E; BSA; bovine serum albumin; C#; complement component #; CEP; carboxyethylpyrrole; CFH; complement factor H; CFHR; complement factor H related protein; CL; cardiolipin; CHD; coronary heart disease; CPS; capsular polysaccharide; CRP; C-reactive protein; CuOx-LDL; copper-oxidized LDL; DAMP(s); damage-associated molecular pattern(s); FAAB; 2-formyl-3-(alkylamino)butanal; HBGM1; high-mobility group box 1; HSP(s); heat shock protein(s); IL-#; interleukin-#; LDL; low-density lipoprotein; MAA; malonacetaldehyde; MDA; malondialdehyde; MDHDC; 4-methyl-1,4-dihydropyridine-3,5-dicarbaldehyde; MFG-E8; Milk fat globule epidermal growth factor 8 (lactadherin); NAb(s); Natural antibodies; OSE(s); oxidation-specific epitope(s); OxCL; oxidized cardiolipin; OxLDL; oxidized LDL; OxPS; oxidized phosphatidylserine; PAMP(s); pathogen-associated molecular pattern(s); PC; phosphocholine; PE; phosphatidylethanolamine; POVPC; 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphcholine; PRR(s); pattern recognition receptor(s); PUFA(s); polyunsaturated fatty acid(s); RAG; recombinase activating gene; TLR#; toll-like receptorLipid peroxidation; Oxidized LDL; Apoptosis; Oxidation-specific epitope; Damage-associated molecular pattern; Pattern recognition receptor

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BBA - Biomembranes (v.1818, #10)