Proteins modified by aldehydes generated from oxidized lipids accumulate in cells during oxidative stress and are commonly detected in diseased or aged tissue. The mechanisms by which cells remove aldehyde-adducted proteins, however, remain unclear. Here, we report that products of lipid peroxidation such as 4-HNE (4-hydroxynonenal) and acrolein activate autophagy in rat aortic smooth-muscle cells in culture. Exposure to 4-HNE led to the modification of several proteins, as detected by anti-protein-4-HNE antibodies or protein-bound radioactivity in [3H]4-HNE-treated cells. The 4-HNE-modified proteins were gradually removed from cells. The removal of 4-HNE-modified proteins was not affected by the oxidized protein hydrolase inhibitor, acetyl leucine chloromethyl ketone, or lactacystin, although it was significantly decreased by PSI (proteasome inhibitor I), the lysosome/proteasome inhibitor MG-132 (carbobenzoxy-L-leucyl-L-leucyl-leucinal), insulin or the autophagy inhibitor 3-MA (3-methyladenine). Pre-incubation of cells with rapamycin accelerated the removal of 4-HNE-modified proteins. Treatment with 4-HNE, nonenal and acrolein, but not nonanal or POVPC (1-palmitoyl-2-oxovaleroyl phosphatidyl choline), caused a robust increase in LC3-II (microtubule-associated protein 1 light chain 3-II) formation, which was increased also by rapamycin, but prevented by insulin. Electron micrographs of 4-HNE-treated cells showed extensive vacuolization, pinocytic body formation, crescent-shaped phagophores, and multilamellar vesicles. Treatment with 3-MA and MG-132, but not proteasome-specific inhibitors, induced cell death in 4-HNE-treated cells. Collectively, these results show that lipid peroxidation-derived aldehydes stimulate autophagy, which removes aldehyde-modified proteins, and that inhibition of autophagy precipitates cell death in aldehyde-treated cells. Autophagy may be an important mechanism for the survival of arterial smooth-muscle cells under conditions associated with excessive lipid peroxidation.

Researchers working in the area of rocket propulsion strive for environmental friendliness, low toxicity, and overall operability, as well as a performance level comparable with current propellant combinations such as hydrazine and N 2 O 4 . Maintaining high performance while lowering hazards is extremely difficult.All rocket oxidizers are hazardous by their very nature, and so reduction of those hazards, even though the resulting materials might not be completely harmless, is at the heart of green initiatives in propulsion. The corrosivity of nitric acid is well known, and, although N 2 O 4 is much less corrosive, it combines high toxicity with high vapor pressure. A significant step to a lower-toxicity bipropulsion system would be the demonstration of hypergolicity (spontaneous ignition) between an ionic liquid (IL), which is a paragon of low vapor toxicity, and a safer oxidizer. Apart from cryogens, hydrogen peroxide seems to be especially promising because of its high performance, less-toxic vapor and corrosivity, and its environmentally benign decomposition products, [1] which make handling this oxidizer considerably less difficult than N 2 O 4 or nitric acid.A high fuel performance can be fostered by light metals with large combustion energies and relatively light products. Elements with considerable performance advantages and nontoxic products are aluminum and boron. The need for light combustion products through the production of hydrogen gas and water vapor is fulfilled by a high hydrogen content. Aluminum and boron are well known for their ability to serve as hydrogen carriers in neutral and ionic molecules. Defense research in the 1960s focused extensively on the development of hydrogen-containing fuels with boron, aluminum, and other metals, [2] but was mainly concerned with neutral compounds that have high vapor toxicity. Their rich anionic chemistry combined with the design flexibility of ILs presage novel materials that have the potential to overcome problems that caused these promising propellants to be abandoned.To date, no IL has been reported to be hypergolic with H 2 O 2 , and first-generation hypergolic ILs based on dicyanamide, nitrocyanamide, and azide anions lack high hydrogen content. [3] We tested ILs from each class with 90 % and 98 % H 2 O 2 , and all failed to ignite. This result is hardly surprising since fuels that are hypergolic with nitric acid vastly outnumber those that ignite with N 2 O 4 . For many years, hydrazine was the only fuel hypergolic with H 2 O 2 . [4] Since solutions of lithium aluminum hydrides and LiBH 4 in ethers have demonstrated H 2 O 2 hypergolicity, [5] the same behavior from ILs with metal hydride anions might be expected. However, the development of energetic roomtemperature ILs (RTILs) with metal hydride anions involves a number of technical challenges. Simple metal hydride anions are poor liquefying agents. Furthermore, heterocyclic, unsaturated salts that feature imidazolium, triazolium, pyridinium, and other common IL cations are reduced by BH 4 À ions,...

OBJECTIVETo examine the role of aldo-keto reductases (AKRs) in the cardiovascular metabolism of the precursors of advanced glycation end products (AGEs).RESEARCH DESIGN AND METHODSSteady-state kinetic parameters of AKRs with AGE precursors were determined using recombinant proteins expressed in bacteria. Metabolism of methylglyoxal and AGE accumulation were studied in human umbilical vein endothelial cells (HUVECs) and C57 wild-type, akr1b3 (aldose reductase)-null, cardiospecific-akr1b4 (rat aldose reductase), and akr1b8 (FR-1)-transgenic mice. AGE accumulation and atherosclerotic lesions were studied 12 weeks after streptozotocin treatment of C57, akr1b3-null, and apoE- and akr1b3-apoE–null mice.RESULTSHigher levels of AGEs were generated in the cytosol than at the external surface of HUVECs cultured in high glucose, indicating that intracellular metabolism may be an important regulator of AGE accumulation and toxicity. In vitro, AKR 1A and 1B catalyzed the reduction of AGE precursors, whereas AKR1C, AKR6, and AKR7 were relatively ineffective. Highest catalytic efficiency was observed with AKR1B1. Acetol formation in methylglyoxal-treated HUVECs was prevented by the aldose reductase inhibitor sorbinil. Acetol was generated in hearts perfused with methylglyoxal, and its formation was increased in akr1b4- or akr1b8-transgenic mice. Reduction of AGE precursors was diminished in hearts from akr1b3-null mice. Diabetic akr1b3-null mice accumulated more AGEs in the plasma and the heart than wild-type mice, and deletion of akr1b3 increased AGE accumulation and atherosclerotic lesion formation in apoE-null mice.CONCLUSIONSAldose reductase–catalyzed reduction is an important pathway in the endothelial and cardiac metabolism of AGE precursors, and it prevents AGE accumulation and atherosclerotic lesion formation.

Phospholipid oxidation generates several bioactive aldehydes that remain esterified to the glycerol backbone ('core' aldehydes). These aldehydes induce endothelial cells to produce monocyte chemotactic factors and enhance monocyte-endothelium adhesion. They also serve as ligands of scavenger receptors for the uptake of oxidized lipoproteins or apoptotic cells. The biochemical pathways involved in phospholipid aldehyde metabolism, however, remain largely unknown. In the present study, we have examined the efficacy of the three mammalian AKR (aldo-keto reductase) families in catalysing the reduction of phospholipid aldehydes. The model phospholipid aldehyde POVPC [1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine] was efficiently reduced by members of the AKR1, but not by the AKR6 or the ARK7 family. In the AKR1 family, POVPC reductase activity was limited to AKR1A and B. No significant activity was observed with AKR1C enzymes. Among the active proteins, human AR (aldose reductase) (AKR1B1) showed the highest catalytic activity. The catalytic efficiency of human small intestinal AR (AKR1B10) was comparable with the murine AKR1B proteins 1B3 and 1B8. Among the murine proteins AKR1A4 and AKR1B7 showed appreciably lower catalytic activity as compared with 1B3 and 1B8. The human AKRs, 1B1 and 1B10, and the murine proteins, 1B3 and 1B8, also reduced C-7 and C-9 sn-2 aldehydes as well as POVPE [1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphoethanolamine]. AKR1A4, B1, B7 and B8 catalysed the reduction of aldehydes generated in oxidized C(16:0-20:4) phosphatidylcholine with acyl, plasmenyl or alkyl linkage at the sn-1 position or C(16:0-20:4) phosphatidylglycerol or phosphatidic acid. AKR1B1 displayed the highest activity with phosphatidic acids; AKR1A4 was more efficient with long-chain aldehydes such as 5-hydroxy-8-oxo-6-octenoyl derivatives, whereas AKR1B8 preferred phosphatidylglycerol. These results suggest that proteins of the AKR1A and B families are efficient phospholipid aldehyde reductases, with non-overlapping substrate specificity, and may be involved in tissue-specific metabolism of endogenous or dietary phospholipid aldehydes.

Oxidation of unsaturated phospholipids results in the generation of aldehyde side chains that remain esterified to the phospholipid backbone. Such "core" aldehydes elicit immune responses and promote inflammation. However, the biochemical mechanisms by which phospholipid aldehydes are metabolized or detoxified are not well understood. In the studies reported here, we examined whether aldose reductase (AR), which reduces hydrophobic aldehydes, metabolizes phospholipid aldehydes. Incubation with AR led to the reduction of 5-oxovaleroyl, 7-oxo-5-heptenoyl, 5-hydroxy-6-oxo-caproyl, and 5-hydroxy-8-oxo-6-octenoyl phospholipids generated upon oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (PAPC). The enzyme also catalyzed the reduction of phospholipid aldehydes generated from the oxidation of 1-alkyl, and 1-alkenyl analogs of PAPC, and 1-palmitoyl-2-arachidonoyl phosphatidic acid or phosphoglycerol. Aldose reductase catalyzed the reduction of chemically synthesized 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphatidylcholine (POVPC) with a K m of 10 M. Addition of POVPC to the culture medium led to incorporation and reduction of the aldehyde in COS-7 and THP-1 cells. Reduction of POVPC in these cells was prevented by the AR inhibitors sorbinil and tolrestat and was increased in COS-7 cells overexpressing AR. Together, these observations suggest that AR may be a significant participant in the metabolism of several structurally diverse phospholipid aldehydes. This metabolism may be a critical regulator of the pro-inflammatory and immunogenic effects of oxidized phospholipids.

Myocardial ischaemia is associated with the generation of lipid peroxidation products such as HNE (4-hydroxy-trans-2-nonenal); however, the processes that predispose the ischaemic heart to toxicity by HNE and related species are not well understood. In the present study, we examined HNE metabolism in isolated aerobic and ischaemic rat hearts. In aerobic hearts, the reagent [3H]HNE was glutathiolated, oxidized to [3H]4-hydroxynonenoic acid, and reduced to [3H]1,4-dihydroxynonene. In ischaemic hearts, [3H]4-hydroxynonenoic acid formation was inhibited and higher levels of [3H]1,4-dihydroxynonene and [3H]GS-HNE (glutathione conjugate of HNE) were generated. Metabolism of [3H]HNE to [3H]4-hydroxynonenoic acid was restored upon reperfusion. Reperfused hearts were more efficient at metabolizing HNE than non-ischaemic hearts. Ischaemia increased the myocardial levels of endogenous HNE and 1,4-dihydroxynonene, but not 4-hydroxynonenoic acid. Isolated cardiac mitochondria metabolized [3H]HNE primarily to [3H]4-hydroxynonenoic acid and minimally to [3H]1,4-dihydroxynonene and [3H]GS-HNE. Moreover, [3H]4-hydroxynonenoic acid was extruded from mitochondria, whereas other [3H]HNE metabolites were retained in the matrix. Mitochondria isolated from ischaemic hearts were found to contain 2-fold higher levels of protein-bound HNE than the cytosol, as well as increased [3H]GS-HNE and [3H]1,4-dihydroxynonene, but not [3H]4-hydroxynonenoic acid. Mitochondrial HNE oxidation was inhibited at an NAD+/NADH ratio of 0.4 (equivalent to the ischaemic heart) and restored at an NAD+/NADH ratio of 8.6 (equivalent to the reperfused heart). These results suggest that HNE metabolism is inhibited during myocardial ischaemia owing to NAD+ depletion. This decrease in mitochondrial metabolism of lipid peroxidation products and the inability of the mitochondria to extrude HNE metabolites could contribute to myocardial ischaemia/reperfusion injury.

Tumor metabolism has been the object of several studies in the past, leading to the pivotal observation of a consistent shift toward aerobic glycolysis (so-called Warburg effect). More recently, several additional investigations proved that tumor metabolism is profoundly affected during tumorigenesis, including glucose, lipid and amino-acid metabolism. It is noticeable that metabolic reprogramming can represent a suitable therapeutic target in many cancer types. Epstein–Barr virus (EBV) was the first virus linked with cancer in humans when Burkitt lymphoma (BL) was described. Besides other well-known effects, it was recently demonstrated that EBV can induce significant modification in cell metabolism, which may lead or contribute to neoplastic transformation of human cells. Similarly, virus-induced tumorigenesis is characterized by relevant metabolic abnormalities directly induced by the oncoviruses. In this article, the authors critically review the most recent literature concerning EBV-induced metabolism alterations in lymphomas.

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