Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We measured the content of lipid peroxides in plasma LDL from patients with chronic CHD not accompanied by hypercholesterolemia; CHD and hypercholesterolemia; type 2 diabetes mellitus and decompensation of carbohydrate metabolism; and CHD, circulatory insufficiency, and type 2 diabetes mellitus (without hypercholesterolemia). The content of lipid peroxides in LDL isolated from blood plasma by differential ultracentrifugation in a density gradient was estimated by a highly specific method with modifications (reagent Fe(2+) xylene orange and triphenylphosphine as a reducing agent for organic peroxides). The content of lipid peroxides in LDL from patients was much higher than in controls (patients without coronary heart disease and diabetes). Hypercholesterolemia and diabetes can be considered as factors promoting LDL oxidation in vivo. Our results suggest that stimulation of lipid peroxidation in low-density lipoproteins during hypercholesterolemia and diabetes is associated with strong autooxidation of cholesterol and glucose during oxidative and carbonyl (aldehyde) stress, respectively. These data illustrate a possible mechanism of the progression of atherosclerosis in patients with diabetes mellitus.
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PMID:Oxidative stress in atherosclerosis and diabetes. 1625 16

4-Hydroxynonenal (HNE) is by far the most investigated aldehydic end-product of oxidative breakdown of membrane n-6 polyunsaturated fatty acids. Its potential involvement in the pathogenesis of atherosclerosis has been corroborated by its consistent detection in both oxidized LDL and fibrotic plaque in humans. HNE has been shown to activate both macrophage and smooth muscle cells, i.e. the two key cell types in chronic inflammatory processes characterized by excessive fibrogenesis. By signalling to the nucleus, the aldehyde may up-regulate in these cells both expression and synthesis of monocyte chemotactic protein 1 (MCP-1) and transforming growth factor beta1 (TGFbeta1). Oxysterols, namely 27 carbon atoms oxidation products of cholesterol, are found in relatively high amount in LDL from hypercholesterolemic individuals and are consistently detectable in foam cells and necrotic core of human atherosclerotic lesion. As for HNE, the challenge of cells of the macrophage lineage with a mixture of oxysterols like that detectable in hypercholesterolemic individuals led to a marked overexpression of TGFbeta1 and MCP-1. Both HNE and oxysterols then appear to be candidates for a primary role in the progression of the atherosclerotic process.
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PMID:4-Hydroxynonenal and cholesterol oxidation products in atherosclerosis. 1627 Feb 77

The calpains represent a well-conserved family of calcium-dependent cysteine proteases. They consist of several ubiquitous and tissue specific isoforms and exhibit broad substrate specificity influencing many aspects of cell physiology including migration, proliferation and apoptosis. Calpain activity in vivo is tightly regulated by its natural endogenous inhibitor calpastatin. Calpastatin specifically inhibits calpain and not other cysteine proteases by interaction with several sites on the calpain molecule. Inappropriate regulation of the calpain-calpastatin proteolytic system is associated with several important human pathological disorders including muscular dystrophy, cancer, Alzheimer's disease, neurological injury, ischaemia/reperfusion injury, atherosclerosis, diabetes and cataract formation. Recent advances in elucidating the tertiary structures of calpain 2 and its regulatory domain calpain 4, together with identification of new modes of regulating calpain activity provide new opportunities for the design of novel calpain inhibitors. Several classes of inhibitors, including peptidyl epoxide, aldehyde, and ketoamide inhibitors, targeting the active site have proven effective against the calpains and are in the process of evaluation in animal models of human disease. However, a major limitation to the clinical use of such inhibitors is their lack of specificity among cysteine proteases and other proteolytic enzymes. The development of a new class of calpain inhibitors that interact with domains outside of the catalytic site of calpain may provide greater specificity and therapeutic potential.
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PMID:Calpain inhibition: a therapeutic strategy targeting multiple disease states. 1647 52

Analysis of trace levels of reactive carbonyl compounds (RCCs), including formaldehyde, acetaldehyde, acrolein, malonaldehyde, glyoxal, and methyl glyoxal, is extremely difficult because they are highly reactive, water soluble, and volatile. Determination of these RCCs in trace levels is important because they are major products of lipid peroxidation, which is strongly associated with various diseases such as cancer, Alzheimer's disease, aging, and atherosclerosis. This review covers the development and application of various derivatives for RCC analysis. Among the many derivatives which have been prepared, cysteamine derivatives for formaldehyde and acetaldehyde; N-hydrazine derivatives for acrolein, 4-hydroxy-2-nonenal, and malonaldeyde; and o-phenylene diamine derivatives for glyoxal and methyl glyoxal were selected for extended discussion. The application of advanced instruments, including gas chromatograph with nitrogen-phosphorus detector (GC/NPD), mass spectrometer (MS), high performance liquid chromatograph (HPLC), GC/MS, and LC/MS, to the determination of trace RCCs in various oxidized lipid samples, including fatty acids, skin lipids, beef fats, blood plasma, whole blood, and liver homogenates, is also discussed.
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PMID:Analytical methods for trace levels of reactive carbonyl compounds formed in lipid peroxidation systems. 1649 70

Increased risk of vasospasm, a spontaneous hyperconstriction, is associated with atherosclerosis, cigarette smoking, and hypertension-all conditions involving oxidative stress, lipid peroxidation, and inflammation. To test the role of the lipid peroxidation- and inflammation-derived aldehyde, acrolein, in human vasospasm, we developed an ex vivo model using human coronary artery bypass graft (CABG) blood vessels and a demonstrated acrolein precursor, allylamine. Allylamine induces hypercontraction in isolated rat coronary artery in a semicarbazide-sensitive amine oxidase activity (SSAO) dependent manner. Isolated human CABG blood vessels (internal mammary artery, radial artery, saphenous vein) were used to determine: (1) vessel responses and sensitivity to acrolein, allylamine, and H(2)O(2) exposure (1 microM-1 mM), (2) SSAO dependence of allylamine-induced effects using SSAO inhibitors (semicarbazide, 1 mM; MDL 72274-E, active isomer; MDL 72274-Z, inactive isomer; 100 microM), (3) the vasoactive effects of two other SSAO amine substrates, benzylamine and methylamine, and (4) the contribution of extracellular Ca(2+) to hypercontraction. Acrolein or allylamine but not H(2)O(2), benzylamine, or methylamine stimulated spontaneous and pharmacologically intractable hypercontraction in CABG blood vessels that was similar to clinical vasospasm. Allylamine-induced hypercontraction and blood vessel SSAO activity were abolished by pretreatment with semicarbazide or MDL 72274-E but not by MDL 72274-Z. Allylamine-induced hypercontraction also was significantly attenuated in Ca(2+)-free buffer. In isolated aorta of spontaneously hypertensive rat, allylamine-induced an SSAO-dependent contraction and enhanced norepinephrine sensitivity but not in Sprague-Dawley rat aorta. We conclude that acrolein generation in the blood vessel wall increases human susceptibility to vasospasm, an event that is enhanced in hypertension.
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PMID:Acrolein generation stimulates hypercontraction in isolated human blood vessels. 1709 30

Acrolein, which is a highly reactive alpha,beta-unsaturated aldehyde generated by lipid peroxidation, can affect cells and tissues and cause various disorders. Increased levels of unsaturated aldehydes play an important role in the pathogenesis of a number of human diseases such as Alzheimer's disease, atherosclerosis and diabetes. Acrolein is a highly ubiquitous toxic environmental pollutant. Because of human exposure, there is a need for investigating the mechanisms involved in acrolein toxicity at the cellular and molecular levels. Acrolein can induce cell death by apoptosis, although the mechanisms are not entirely clear. The present study investigates whether mitogen-activated protein kinases (MAPKs) play a role in activation of apoptosis by acrolein. Our findings show that acrolein-mediated apoptosis is in fact MAPK-dependent in Chinese hamster ovary cells. The MAP family kinases, including ERK and p38 kinase, and the transcription factor c-Jun were all activated by phosphorylation after 1 h exposure to acrolein. Phosphorylation of ERK and p38 kinases and their blockade by an ERK inhibitor, U0126, or a p38 inhibitor, SB203580, respectively, suggested that activation of apoptosis by acrolein is ERK- and p38-dependent. Thus, blockade of ERK and p38 inhibited chromatin condensation, caspase-7 and -9 activation as well as ICAD cleavage induced by acrolein. JNK and AKT kinases seem to be implicated in survival pathways against acrolein insult, since their respective inhibitors, SP600125 and LY294002/Wortmannin switched the mode of cell death from apoptosis to total necrosis. Finally, acrolein induced phosphorylation of the pro-apoptotic factor p53 which is responsible for transcription of pro-apoptotic factors such as Bax and Fas ligand. These results provide new information demonstrating the implication of MAPKs and AKT in acrolein-induced apoptosis, and this information may be useful for understanding the pathogenesis of a number of tissue diseases and environmental toxicity in response to acrolein.
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PMID:P38 and ERK mitogen-activated protein kinases mediate acrolein-induced apoptosis in Chinese hamster ovary cells. 1719 91

Reactive alpha,beta-unsaturated aldehydes such as acrolein are major components of common environmental pollutants. As a toxic by-product of lipid peroxidation, acrolein has been implicated as a possible mediator of oxidative damage to cells and tissues in a wide variety of disease states, including atherosclerosis and neurodegenerative and pulmonary diseases. Although acrolein can induce apoptotic cell death in various cell types, the biochemical mechanisms are not understood. This study investigates the implication of the death receptor pathway in acrolein-induced apoptosis. Exposure of Chinese hamster ovary cells to acrolein caused translocation of adaptor protein Fas associated with death domain to the cytoplasmic membrane and caspase-8 activation. Kp7-6, an antagonist of Fas receptor activation, blocked apoptotic events downstream of caspase-8, such as caspase-7 activation and nuclear chromatin condensation. Acrolein activated the cross-talk pathway between the death receptor and mitochondrial pathways. Bid was cleaved to truncated-Bid, which was translocated to mitochondria. Activation of the mitochondrial pathway by acrolein was confirmed by caspase-9 activation. Inhibition of activation of either the Fas receptor or caspase-8 partially decreased acrolein-induced caspase-9 activation. These findings indicate that acrolein activates the Fas receptor pathway, which occurs upstream of the mitochondrial pathway. Caspase-9 activation still occurred despite inhibition of the Fas receptor pathway, suggesting that acrolein could also trigger the mitochondrial pathway independent of the receptor pathway. These findings improve our understanding of mechanisms of toxicity of the reactive aldehyde acrolein, which has widespread implications in multiple disease states which seem to be mediated by oxidative stress and lipid peroxidation.
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PMID:Activation of the death receptor pathway of apoptosis by the aldehyde acrolein. 1732 Jul 62

Reactive aldehydes and ketones are produced as a result of oxidative stress in several disease processes. Considerable evidence is now accumulating that these reactive carbonyl products are also involved in the progression of diseases, including neurodegenerative disorders, diabetes, atherosclerosis, diabetic complications, reperfusion after ischemic injury, hypertension, and inflammation. To counter carbonyl stress, cells possess enzymes that can decrease aldehyde load. These enzymes include aldehyde dehydrogenases (ALDH), aldo-keto reductases (AKR), carbonyl reductase (CBR), and glutathione S-transferases (GST). Some of these enzymes are inducible by chemoprotective compounds via Nrf2/ARE- or AhR/XRE-dependent mechanisms. This review describes the metabolism of reactive carbonyls and discusses the potential for manipulating levels of carbonyl-metabolizing enzymes through chemical intervention.
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PMID:Reactive carbonyls and oxidative stress: potential for therapeutic intervention. 1757 May 31

The vascular diseases, hypertension and atherosclerosis, affect millions of individuals worldwide, and account for a large number of deaths globally. A better understanding of the mechanism of these conditions will lead to more specific and effective therapies. Hypertension and atherosclerosis are both characterized by insulin resistance, and we suggest that this plays a major role in their etiology. The cause of insulin resistance is not known, but may be a result of a combination of genetic and lifestyle factors. In insulin resistance, alterations in glucose and lipid metabolism lead to the production of excess aldehydes including glyoxal and methylglyoxal. These aldehydes react non-enzymatically with free amino and sulfhydryl groups of amino acids of proteins to form stable conjugates called advanced glycation end products (AGEs). AGEs act directly, as well as via receptors to alter the function of many intra- and extracellular proteins including antioxidant and metabolic enzymes, calcium channels, lipoproteins, and transcriptional and structural proteins. This results in endothelial dysfunction, inflammation and oxidative stress. All these changes are characteristic of hypertension and atherosclerosis. Human and animal studies have demonstrated that increased AGEs are also associated with these conditions. A pathological role for AGEs is substantiated by studies showing that therapies that attenuate insulin resistance and/or lower AGEs, are effective in decreasing oxidative stress, lowering blood pressure, and attenuating atherosclerotic vascular changes. These interventions include lipoic acid and other antioxidants, AGE breakers or soluble receptors of AGEs, and aldehyde-binding agents like cysteine. Such therapies may offer alternative specific means to treat hypertension and atherosclerosis. An adjunct therapy may be to implement lifestyle changes such as weight reduction, regular exercise, smoking cessation, and increasing dietary intake of fruits and vegetables that also decrease insulin resistance as well as oxidative stress.
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PMID:Role of advanced glycation end products in hypertension and atherosclerosis: therapeutic implications. 1787 39

Habitual consumption of some Melanesian medicinal and food plants may influence atherosclerosis development via their antioxidant capacity at the endothelial level. Areca nut (AN; Areca catechu), piper inflorescence (PBI; Piper betle), betel quid (BQ), guava buds (GB; Psidium guajava), the leaves (NL), juice (NJ), fruit (NF), and root (NR) of noni (Morinda citrifolia), the propagules of raw (MBR), and cooked (MBC) mangrove (Bruguiera gymnorrhiza) were evaluated for their ability to scavenge the 1,1-diphenyl-2-picryl-hydrazyle (DPPH) radical, to protect human low-density lipoprotein (LDL) from Cu2+-catalyzed oxidation and to protect cultured bovine aortal endothelial cells (BAEC) from oxidized LDL (oxLDL)-induced cytotoxicity. Polyphenol-rich extracts AN, PBI, and BQ were potent DPPH scavengers, having similar activity to quercetin and able to protect LDL from oxidation in a dose-dependent manner at concentrations higher than 10 microg/mL, but were pro-oxidants at lower concentrations. These extracts were cytotoxic to BAEC at concentrations above 10 microg/mL and were unable to prevent oxLDL endotheliopathy. GB and NR at 10 mug/mL displayed both the ability to delay LDL oxidation and prevent oxLDL cytotoxicity, although the latter lacked the ability to scavenge the DPPH radical. At higher concentrations, however, both were cytotoxic in themselves. The remaining noni extracts NF, NJ, NL, and both mangrove extracts MBC and MBR were unable to protect LDL from oxidation at all tested concentrations, but were effective cytoprotective agents at 50 microg/mL. All extracts were able to prevent an oxLDL-mediated increase in intracellular aldehyde generation but had little effect on extracellular peroxidation as measured by thiobarbituric acid reactive substances (TBARS). On the basis of this model system, we conclude that the antioxidant benefits of AN, PBI, and BQ may be offset by their enhancement of their cytotoxic effects of oxLDL toward BAEC, whereas GB and low concentrations of noni and mangrove may be considered antiatherogenic. The discrepancies between our in vitro and cellular culture experiments emphasize the importance of experimental conditions in evaluating the antioxidant potential of crude plant extracts.
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PMID:Endothelial cytoprotection from oxidized LDL by some crude Melanesian plant extracts is not related to their antioxidant capacity. 1791


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