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)

Advanced glycation end products (AGEs), formed during Maillard or browning reactions by nonenzymatic glycation and oxidation (glycoxidation) of proteins, have been implicated in the pathogenesis of several diseases, including diabetes and uremia. AGEs, such as pentosidine and carboxymethyllysine, are markedly elevated in both plasma proteins and skin collagen of uremic patients, irrespective of the presence of diabetes. The increased chemical modification of proteins is not limited to AGEs, because increased levels of advanced lipoxidation end products (ALEs), such as malondialdehydelysine, are also detected in plasma proteins in uremia. The accumulation of AGEs and ALEs in uremic plasma proteins is not correlated with increased blood glucose or triglycerides, nor is it determined by a decreased removal of chemically modified proteins by glomerular filtration. It more likely results from increased plasma concentrations of small, reactive carbonyl precursors of AGEs and ALEs, such as glyoxal, methylglyoxal, 3-deoxyglucosone, dehydroascorbate, and malondialdehyde. Thus, uremia may be described as a state of carbonyl overload or "carbonyl stress" resulting from either increased oxidation of carbohydrates and lipids (oxidative stress) or inadequate detoxification or inactivation of reactive carbonyl compounds derived from both carbohydrates and lipids by oxidative and nonoxidative chemistry. Carbonyl stress in uremia may contribute to the long-term complications associated with chronic renal failure and dialysis, such as dialysis-related amyloidosis and accelerated atherosclerosis. The increased levels of AGEs and ALEs in uremic blood and tissue proteins suggest a broad derangement in the nonenzymatic biochemistry of both carbohydrates and lipids.
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PMID:Alterations in nonenzymatic biochemistry in uremia: origin and significance of "carbonyl stress" in long-term uremic complications. 998 64

Glycoxidative damage in the vasculature has been linked to atherosclerotic cardiovascular disease. Estrogens protect against the development and progression of atherosclerosis. Because estrogens are potent antioxidants that also effect glucose metabolism, part of their protection against atherosclerosis could be through attenuation of glycoxidative damage in the vascular wall. In this study, we tested the hypothesis that chronic estradiol administration is associated with decreased levels of glycoxidative damage in arterial walls. We harvested and examined iliac arteries from ovariectomized, 8-month-old rats that had been implanted for 6 months with 1 of the following subcutaneous hormone pellets: low estradiol (2.5 mg estradiol), high estradiol (25 mg estradiol), P4 (200 mg progesterone), low estradiol and P4, placebo (no hormone), or control (no implant). Using pentosidine as a biomarker of glycoxidative damage, we found that all vessels from rats receiving estradiol (low estradiol, high estradiol, and low estradiol+P4) exhibited a 50% reduction in glycoxidative damage compared with P4, placebo, and control vessels (P<0.05). Consistent with this finding, we observed that estradiol-treated rats had a 30% decrease in tissue levels of hydroperoxides, a marker of oxidative stress. Finally, estradiol-treated rats had a small, but significant, decrease in plasma glucose levels (P<0.01). In summary, we report the novel finding that chronic estrogen administration is associated with significant decreases in glycoxidative damage and oxidative stress in the arterial wall. It seems likely that these actions may constitute a mechanism by which estrogen attenuates the progression of atherosclerosis.
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PMID:17 beta-estradiol reduces glycoxidative damage in the artery wall. 1019 7

Chronic uremia appears to be in a state of an increased oxidative stress. Under oxidative stress, proteins are modified directly by reactive oxygen species with the eventual formation of oxidised amino acids. Proteins are also modified indirectly with reactive carbonyl compounds formed by the autoxidation of carbohydrates and lipids, with the eventual formation of the advanced glycation/lipoxidation end products (AGEs/ALEs). AGEs, pentosidine and carboxymethyllysine (CML), and ALE, malondialdehyde (MDA)-lysine, are elevated in plasma and matrix proteins of uremic patients several times above normal subjects. Precursor carbonyl compounds derived from carbohydrates and lipids are indeed elevated in uremic circulation. Uremia thus appears to be in a state of carbonyl overload with potentially damaging proteins (carbonyl stress). Carbonyl stress might be relevant to long-term complications associated with chronic renal failure and dialysis, such as dialysis-related amyloidosis and atherosclerosis. Immunohistochemical studies identified carbonyl stress in long-lived amyloid deposits and vascular lesions. Proteins modified under carbonyl stress exhibit several biological activities, which might, at least in part, account for the development of joint and vascular complications in uremia.
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PMID:Oxidative protein damage with carbohydrates and lipids in uremia: 'Carbonyl stress'. 1044 66

The implication of advanced glycation end products (AGE) in the pathogenesis of atherosclerosis and of diabetic and uremic complications has stimulated a search for AGE inhibitors. This study evaluates the AGE inhibitory potential of several well-tolerated hypotensive drugs. Olmesartan, an angiotensin II type 1 receptor (AIIR) antagonist, as well as temocaprilat, an angiotensin-converting enzyme (ACE) inhibitor, unlike nifedipine, a calcium blocker, inhibit in vitro the formation of two AGE, pentosidine and N(epsilon)-carboxymethyllysine (CML), during incubation of nonuremic diabetic, nondiabetic uremic, or diabetic uremic plasma or of BSA fortified with arabinose. This effect is shared by all tested AIIR antagonists and ACE inhibitors. On an equimolar basis, they are more efficient than aminoguanidine or pyridoxamine. Unlike the latter two compounds, they do not trap reactive carbonyl precursors for AGE, but impact on the production of reactive carbonyl precursors for AGE by chelating transition metals and inhibiting various oxidative steps, including carbon-centered and hydroxyl radicals, at both the pre- and post-Amadori steps. Their effect is paralleled by a lowered production of reactive carbonyl precursors. Finally, they do not bind pyridoxal, unlike aminoguanidine. Altogether, this study demonstrates for the first time that widely used hypotensive agents, AIIR antagonists and ACE inhibitors, significantly attenuate AGE production. This study provides a new framework for the assessment of families of AGE-lowering compounds according to their mechanisms of action.
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PMID:Angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors lower in vitro the formation of advanced glycation end products: biochemical mechanisms. 1223 36

Cardiovascular disease (CVD) is the leading cause of mortality in end-stage renal disease (ESRD) patients and there is emerging evidence that genetic factors may contribute to the development of atherosclerosis. Myeloperoxidase (MPO) is an abundant enzyme involved in the production of free radicals. A functional G-->A single nucleotide polymorphism (SNP) has been identified at position -463, where the A allele is associated with lower MPO expression. To analyze the association between this SNP and inflammation, oxidative stress, and CVD, we studied a cohort of 155 ESRD patients (52 +/- 1 years, 62% males, 22% diabetics) shortly before the initiation of dialysis treatment. CVD was defined by medical history criteria; plasma interleukin-6 (IL-6) was used as a marker of inflammation, and plasma pentosidine as an estimation of oxidative protein damage. DNA from leukocytes was used for genotyping, performed by the pyrosequencing reaction. Only five patients (3%) had the genotype AA at the -463 position, whereas 38 (25%) had the GA and 112 (72%) had the GG genotype. No differences were noted in plasma IL-6 levels between the genotype groups, whereas the pentosidine levels were higher in the GG group (28.4 pmol/mg albumin [range, 8.5 to 123 pmol/mg albumin]) compared to the other two groups (21.4 pmol/mg albumin [range, 7.6 to 384 pmol/mg albumin; P < 0.05]). Patients with the GG genotype had a higher prevalence of positive serology for Chlamydia pneumoniae (51%) when compared to the carriers of the A allele (24%) (P < 0.05). The prevalence of CVD was lower in the AA (0%) and GA genotypes (18%), compared to the GG genotype (35%). The GG genotype was still associated with CVD after correction for age, diabetes, smoking, malnutrition, and inflammation. Our findings suggest that the -463 G-->A SNP, which supposedly results in lower MPO activity, is associated with a lower prevalence of CVD in ESRD patients. It could be speculated that this effect is mediated by a decreased oxidative stress due to lower production of free radicals.
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PMID:A functional variant of the myeloperoxidase gene is associated with cardiovascular disease in end-stage renal disease patients. 1284 78

Maillard reactions have been explored by food chemists for many years. It is only recently that the advanced glycation end products (AGEs), the end products of the Maillard reaction, have been detected in a wide variety of diseases such as diabetes, atherosclerosis, cataractogenesis, Parkinson disease and Alzheimer disease (AD). In this review, we discuss the chemistry and biochemistry of AGE-related crosslinks such as pyrraline, pentosidine, carboxymethyllysine (CML), crosslines, imidazolidinones, and dilysine crosslinks (GOLD and MOLD), as well as their possible involvement in neurodegenerative conditions. Pentosidine and CML are found in elevated amounts in the major lesions of the AD brain. Glycation is also implicated in the formation of the paired helical filaments (PHF), a component of the neurofibrillary tangles (NFTs). Amyloid-beta peptide and proteins of the cerebrospinal fluid are also glycated in patients with AD. In order to ameliorate the effects of AGEs on AD pathology, various inhibitors of AGEs have been increasingly explored. It is hoped that understanding of the mechanism of the AGEs formation and their role in the neurodegeneration will result in novel therapeutics for neuroprotection.
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PMID:Involvement of Maillard reactions in Alzheimer disease. 1282

Immunological approaches have been used to demonstrate the presence of advanced glycation end-products (AGEs) in several human and experimental animal tissues. We previously prepared polyclonal and monoclonal anti-AGE antibodies by immunizing AGE-modified proteins such as BSA and RNase. Although these antibodies contributed to demonstrate the presence of AGE-modified protein in vivo, the epitope structure of these antibodies had not been identified. We subsequently prepared several antibodies against AGE structures such as pentosidine, pyrraline, 3-deoxyglucosone imidazolone and N epsilon-(carboxyethyl)lysine by immunizing single AGE structures. These structure-specific antibodies have greatly helped broaden our understanding of AGE structures in aging and age-enhanced disease process. Monoclonal anti-AGE antibody is also used for the identification of major AGE structures in some pathological tissues, such as human atherosclerosis lesions. Based on the strategy, we successfully identified a novel AGE structure named glycolaldehyde-pyridine, which is the major antigenic AGE derived from glycolaldehyde. Therefore a monoclonal antibody library for AGE structures has served an important role in the elucidation of the biological significance of AGE.
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PMID:Application of monoclonal antibody libraries for the measurement of glycation adducts. 1464 Oct 83

Advanced glycation end-products (AGEs), a group of carbohydrate-derived compounds formed by non-enzymatic glycation and oxidation, are markedly elevated in end-stage renal disease (ESRD) and may be related to both inflammation and oxidative stress. The cellular effects of AGE are largely mediated by their interaction with specific surface receptors, such as RAGE. Measurements of biomarkers of inflammation and oxidative stress were conducted in 7 hemodialysis (HD) patients (5 males) with persistent high-grade inflammation (C-reactive protein [CRP]>10 mg/L) and 11 HD-patients (6 males) with low-grade inflammation (CRP<10 mg/L) for at least 6 months. Measured biomarkers for inflammation included hs-CRP, interleukin (IL)-6, white blood cells, neutrophils, S-albumin, peroxisome proliferator-activated receptors (PPAR alpha, beta, gamma) and nuclear factor kappaB (NFkappaB) activity. Markers for oxidative stress were advanced oxidation products (AOPP), myeloperoxidase (MPO)-activity, pentosidine and carboxymethyl lysine (CML). In addition, the effect of increasing doses of CML-modified human serum albumin on NFkappaB activity was tested in mononuclear cells isolated from each patient. As expected, HD-patients with high-grade inflammation had significantly elevated levels of IL-6 (median 9.2 pg/mL versus 2.5 pg/mL; p<0.01), MPO-activity (134.5+/-14.6 DeltaOD(630)/(min mg protein) versus 80.5+/-12.9 DeltaOD(630)/(min mg protein); p<0.05), PPAR-gamma (0.65+/-0.01 OD(655) versus 0.56+/-0.01 OD(655); p<0.01), and AOPP (269+/-54 microM versus 163+/-15 microM; p<0.05) compared with low-grade inflamed patients. Significant associations were demonstrated between hs-CRP and NFkappaB (rho=0.58; p<0.05), AOPP (rho=0.49; p<0.05) and PPAR-gamma (rho=0.62; p<0.05), respectively. In the patient group with high-grade inflammation, stimulation of mononuclear cells with CML-modified human serum albumin caused a rapid dose-dependent rise (p<0.0001) in NFkappaB activity that could be completely blocked by an anti-RAGE antibody. Inflammation and oxidative stress biomarkers are interrelated in ESRD. Inflammatory cell signal pathways, such as NFkappaB, are activated by CML-modification of proteins via RAGE.
Atherosclerosis 2005 Jun
PMID:Enhanced RAGE-mediated NFkappaB stimulation in inflamed hemodialysis patients. 1591 Aug 60

Several diseases (atherosclerosis, diabetes mellitus, chronic renal failure) are associated with oxidative and carbonyl stress, microinflammation and eventually autoimmune reaction. Both oxidative and carbonyl stress cause damage to important biological structures-proteins, carbohydrates, lipids and nucleic acids and may enhance inflammatory response. New compounds and modified structures are formed, among them advanced oxidation protein products (AOPP), advanced glycation end products (AGEs-e.g. pentosidine, carboxymethyllysine) and advanced lipoperoxidation end products (ALEs). Accumulation of glycoxidation products, upregulation of protective mechanisms like glyoxalase I as well as enhanced transcription of genes coding for cytokines, growth factors and adhesive molecules via AGE-RAGE (receptor for AGEs) interaction and subsequent increase of classical acute phase reactants (e.g. CRP-C-reactive protein or orosomucoid) can be observed in a variety of chronic diseases. Additionally, several RAGE gene polymorphisms have shown association with some pathological states-diabetic complications, vascular damage, inflammatory response or antioxidant status. Recent advances in understanding the pathogenesis of chronic diseases provide new possibilities for diagnostics and monitoring of severely ill patients, however, further studies are still required to establish efficient therapeutical strategies.
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PMID:Advanced glycoxidation end products in chronic diseases-clinical chemistry and genetic background. 1608 33

Free radical-mediated oxidative damage and consequent protein modification by the end products of oxidative damage are important mediators of cell toxicity and disease pathogenesis. Aldehydic products, mainly the 4-hydroxy-2-alkenals, form adducts with proteins and make them highly immunogenic. Oxidative modification of proteins has been shown to elicit antibodies in a variety of diseases including systemic lupus erythematosus (SLE), alcoholic liver disease, diabetes mellitus (DM), and rheumatoid arthritis (RA). Oxidatively modified DNA (8-oxodeoxyguanine) and low-density lipoproteins (LDL) occur in SLE, a disease in which premature atherosclerosis is a serious problem. In addition, immunization with 4-hydroxy-2-nonenal (HNE)-modified 60-kDa Ro autoantigen elicits an accelerated epitope spreading in an animal model of SLE. Advanced glycation end product (AGE) pentosidine and AGE-modified IgG have been shown to correlate with RA disease activity. Oxidatively modified glutamic acid decarboxylase is important in type 1 DM, while autoantibodies against oxidized LDL are prevalent in Behcet's disease. The fragmentation of scleroderma-specific autoantigens occurs as a result of oxidative modification and is thought to be responsible for the production of autoantibodies through the release of cryptic epitopes. In the face of overwhelming evidence for the involvement of oxidative damage in autoimmunity the administration of antioxidants is a viable untried alternative for preventing or ameliorating autoimmune disease, although results in cardiovascular disease are disappointing.
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PMID:Oxidatively modified autoantigens in autoimmune diseases. 1686 87


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