Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Advanced glycation endproducts have been implicated in a number of diabetic and aging changes. Some of these effects occur in part through induction of cytokines such as platelet-derived growth factor (PDGF), which is expressed by the retinal pigment epithelium (RPE). In this study, cultures of RPE were evaluated for PDGF expression after treatment with pentosidine, a well characterized advanced glycation endproduct. Northern analysis provided evidence for the increased expression of a 3.7 kb PDGF-B transcript over unstimulated controls in the established ARPE-19 cell line. Western analysis demonstrated increased PDGF-BB protein in conditioned medium compared to controls of ARPE-19 cells. In addition, two different early passage cultures of RPE showed increased PDGF-BB protein after pentosidine treatment compared to unstimulated controls. The enhanced production of PDGF-BB could play a role in the maintenance of the RPE-Bruch's membrane complex and influence changes associated with diabetes and aging.
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PMID:The advanced glycation endproduct pentosidine induces the expression of PDGF-B in human retinal pigment epithelial cells. 959 35

Dysfunction of the vascular endothelium is considered an early step in the development of diabetic angiopathy. Hyperglycaemia results in endothelial dysfunction, both through direct effects of glucose and through formation of advanced glycosylation end-products (AGEs). We hypothesized that the effects of glucose and AGEs on endothelial function in insulin-dependent diabetes mellitus (IDDM) are distinct and are reflected by distinct plasma markers of endothelial function. We therefore measured plasma levels of von Willebrand factor (vWF), soluble (s) E-selectin and vascular cell adhesion molecule-1 (sVCAM-1), and evaluated the relationship with HbA1c and urinary excretion of pentosidine, an AGE product, in 56 patients with IDDM. Urinary pentosidine excretion was higher in the diabetic than in a control group (n = 60) of similar age (P < 0.0001) and showed a steeper increase with age (P < 0.02 vs controls). In the diabetic group, sE-selectin was correlated to HbA1c (r = 0.52, P < 0.0001), whereas sVCAM-1 was not (r = 0.11, P = 0.47). In contrast, sVCAM-1 showed a trend towards a correlation with log (pentosidine excretion) (r = 0.27, P = 0.06), whereas sE-selectin did not (r = -0.16, P = 0.27). Log(vWF) was correlated to HbA1c (r = 0.50, P < 0.0001) and tended to correlate with log (pentosidine excretion) (r = 0.25, P = 0.07). Multivariate analyses with both pentosidine and HbA1c as independent variables showed significant associations of sE-selectin with HbA1c, of sVCAM-1 with pentosidine, and of log(vWF) with both HbA1c and pentosidine (all P-values < 0.02). Our results imply that the effects of glucose and AGEs on the endothelium can be reflected by distinct endothelial markers. Plasma sE-selectin may reflect short-term effects of glucose on the endothelium, sVCAM-1 the effects of AGEs, and vWF the combined effect of glucose and AGEs.
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PMID:Distinct associations of HbA1c and the urinary excretion of pentosidine, an advanced glycosylation end-product, with markers of endothelial function in insulin-dependent diabetes mellitus. 968 85

Nonenzymatic reactions between glucose and proteins yield advanced glycation end products (AGE) such as pentosidine. AGE accumulate in diabetic patients, alter the structure and function of tissue proteins, stimulate cellular response, and have thus been implicated in diabetic tissue damage. The present study was undertaken to assess the factors determining plasma total pentosidine level in diabetic patients and the possible relation between plasma pentosidine level and diabetic complications. In diabetic patients, including patients with renal failure, plasma pentosidine levels, assessed by HPLC assay, were correlated with serum creatinine (P < 0.0001). In patients with normal renal function, pentosidine levels were correlated with blood glucose control (hemoglobin Alc: P = 0.0028; fructoselysine: P = 0.0133), serum creatinine (P = 0.029), patient age (P = 0.0416), duration of diabetes (P = 0.0431), and total cholesterol (P = 0.0056) and LDL-cholesterol (P = 0.0208). Multiple regression analysis revealed an independent influence of hemoglobin Alc and serum creatinine on pentosidine levels (r2 = 0.216, P = 0.0026). Pentosidine levels were higher in patients with than in those without hypertension (P = 0.043) or ischemic heart diseases (P = 0.0061). No such differences were observed between patients with and without albuminuria or retinopathy. Multiple regression analysis revealed an independent influence of plasma pentosidine on the presence of hypertension (r2 = 0.129, P = 0.0382) and of plasma pentosidine and HDL-cholesterol on the presence of ischemic heart disease (r2 = 0.326, P = 0.0012). The present study demonstrated that plasma pentosidine level was significantly influenced by the quality of glycemic control and renal function. Pentosidine level was also correlated with hypertension and ischemic heart disease, and might be taken as a biomarker of diabetic cardiovascular risk.
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PMID:Plasma levels of pentosidine in diabetic patients: an advanced glycation end product. 972 77

1. The role of oxidative stress in the pathogenesis of the diabetic state is being investigated extensively. Although oxidative stress has been reported in terms of glycoxidation, protein oxidation and DNA oxidation in diabetes mellitus, oxidation parameters have not been determined in parallel on the same study population.2. We studied 24 patients with diabetes mellitus (14 patients with Type I diabetes with a mean age of 62.3+/-6.3 years and 10 patients with Type II diabetes aged 67.3+/-5.9 years) and compared them with age-matched non-diabetic controls. Urinary o-tyrosine, 8-hydroxy-2'-deoxyguanosine and pentosidine measurements by HPLC were made on two occasions (t1 and t2).3.A clear statistical difference was found between diabetic patients and controls at t1 or t2 for 8-hydroxy-2'-deoxyguanosine and pentosidine, but not for o-tyrosine. No significant correlations were found between clinical and other laboratory parameters except high-density lipoprotein and uric acid. We revealed significantly increased glycoxidation and DNA oxidation in patients with Type I and Type II diabetes, but protein oxidation was not different from controls.4. The finding of increased glycoxidation reflects increased oxidation of the carbohydrate moiety, whereas the increased levels of oxidized DNA may also be interpreted as due to increased DNA repair. The increased 8-hydroxy-2'-deoxyguanosine does not indicate the generation of an individual active oxygen species, but DNA could have been oxidized simply by alkenals from lipid peroxidation, as e.g. malondialdehyde. As no difference in protein oxidation (i.e. o-tyrosine) between diabetics and controls could be revealed, the oxidation of DNA by hydroxyl radical attack is unlikely, as o-tyrosine was proposed as a marker for hydroxyl radical attack. Therefore, the message is that increased glycoxidation can be confirmed, protein oxidation does not appear to take place and increased DNA oxidation is still not proven, as increased 8-hydroxy-2'-deoxyguanosine may simply reflect repair.
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PMID:Glycoxidation, and protein and DNA oxidation in patients with diabetes mellitus. 973 Aug 53

The formation of Maillard products is increased in the diabetes mellitus. These advanced glycated end products (AGEs) alter metabolic functions of macromolecules and increase free radical formation while decreasing free radical-scavenging enzyme activity. The elimination of AGEs is insured by the macrophage cells equipped with appropriate receptors (RAGE) and cleared by kidneys. The knowledge of these molecular mechanisms had allowed the emergence of biochemical analytes such as 3-deoxyglucosone, pentosidine, and carboxymethyl-lysine, as markers of the ris of micro- and macro-angiopathy, the main chronic complications of the diabetes mellitus.
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PMID:[Role of Maillard products in the chronic complications of diabetes mellitus. Bioclinical applications]. 980 17

Although the involvement of oxidative stress is well documented in the diabetic state, the individual active oxygen species generated have not been demonstrated in animal models of diabetes currently used. Since streptozotocin-induced diabetes mellitus in animals still serves as an animal model of diabetes mellitus, but streptozotocin induces diabetes and generates oxidative stress per se, we decided to study whether aromatic hydroxylation reflecting hydroxyl radical attack was found in three animal models of diabetes mellitus without streptozotocin induction or in streptozotocin-induced diabetes only. For this purpose, we compared lipid peroxidation, aromatic hydroxylation of phenylalanine, glycoxidation in genetically determined diabetic mouse strains db/db and kk, and the diabetic BB rat to these parameters in the streptozotocin-treated rat. Kidney malondialdehyde concentrations, reflecting lipid peroxidation, pentosidine, and Nepsilon-caboxymethyllysine concentrations, reflecting glycoxidation, were significantly elevated in all diabetic groups as compared to their nondiabetic mates. Aromatic hydroxylation was significantly elevated in the streptozotocin-induced diabetic state exclusively. We conclude that biochemical, pathophysiological, and treatment studies in the streptozotocin model of diabetes mellitus may be confounded by the presence of products, reactions, and tissue damage generated by aromatic hydroxylation reflecting hydroxyl radical attack. We suggest it is not the diabetic state but streptozotocin that generates the hydroxyl radical, as reflected by aromatic hydroxylation in this model.
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PMID:Aromatic hydroxylation in animal models of diabetes mellitus. 980 67

Methylglyoxal is formed in vivo by spontaneous decomposition of triose phosphate intermediates in aerobic glycolysis. It may also be formed during oxidative degradation of both carbohydrates (pentoses and ascorbate) and lipids (arachidonate). In addition to reaction with arginine residues to form imidazolone adducts, methylglyoxal reacts with lysine residues in protein to form N(epsilon)-(carboxyethyl)lysine (CEL) and the imidazolium crosslink, methylglyoxal-lysine dimer (MOLD). Like the glycoxidation products, N(epsilon)-(carboxymethyl)lysine (CML) and glyoxal-lysine dimer (GOLD) which are formed on reaction of glyoxal with protein, CEL and MOLD increase in lens proteins and skin collagen with age. CML and CEL also increase in skin collagen in diabetes, while all four compounds increase in plasma proteins in uremia. Overall, CML, CEL, GOLD and MOLD are quantitatively the major biomarkers of the Maillard reaction in tissue proteins. GOLD and MOLD, in particular, are present at 10-50 fold higher concentrations than the fluorescent crosslink, pentosidine. Together, these dicarbonyl-derived advanced glycation endproducts (AGEs) represent the major chemical modifications that accumulate in tissue proteins with age and in chronic diseases such as diabetes and atherosclerosis.
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PMID:Chemical modification of proteins by methylglyoxal. 984 96

Advanced glycation end product (AGE) formation is related to hyperglycemia in diabetes but not in uremia, because plasma AGE levels do not differ between diabetic and nondiabetic hemodialysis patients. The mechanism of this phenomenon remains elusive. Previously, it was suggested that elevation of AGE levels in uremia might result from the accumulation of unknown AGE precursors. The present study evaluates the in vitro generation of pentosidine, a well identified AGE structure. Plasma samples from healthy subjects and nondiabetic hemodialysis patients were incubated under air for several weeks. Pentosidine levels were determined at intervals by HPLC assay. Pentosidine rose to a much larger extent in uremic than in control plasma. Pentosidine yield, i.e., the change in pentosidine level between 0 and 4 wk divided by 28 d, averaged 0.172 nmol/ml per d in uremic versus 0.072 nmol/ml per d in control plasma (P < 0.01). The difference in pentosidine yield between uremic and control plasma was maintained in samples ultrafiltrated through a filter with a 5000-Da cutoff value and fortified with human serum albumin (0.099 versus 0.064 nmol/ml per d; P < 0.05). Pentosidine yield was higher in pre- than in postdialysis plasma samples (0.223 versus 0.153 nmol/ml per d; P < 0.05). These results suggest that a large fraction of the pentosidine precursors accumulated in uremic plasma have a lower than 5000 Da molecular weight. Addition of aminoguanidine and OPB-9195, which inhibit the Maillard reaction, lowered pentosidine yield in both uremic and control plasma. When ultrafiltrated plasma was exposed to 2,4-dinitrophenylhydrazine, the yield of hydrazones, formed by interaction with carbonyl groups, was markedly higher in uremic than in control plasma. These observations strongly suggest that the pentosidine precursors accumulated in uremic plasma are carbonyl compounds. These precursors are unrelated to glucose or ascorbic acid, whose concentration is either normal or lowered in uremic plasma. They are also unrelated to 3-deoxyglucosone, a glucose-derived dicarbonyl compound whose level is raised in uremic plasma: Its addition to normal plasma fails to increase pentosidine yield. This study reports an elevated level of reactive carbonyl compounds ("carbonyl stress") in uremic plasma. Most have a lower than 5000 Da molecular weight and are thus partly removed by hemodialysis. Their effect on pentosidine generation can be inhibited by aminoguanidine or OPB-9195. Carbonyl stress might contribute to AGE modification of proteins and thus to clinically relevant complications of uremia.
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PMID:Accumulation of carbonyls accelerates the formation of pentosidine, an advanced glycation end product: carbonyl stress in uremia. 984 90

The cheetah (Acinonyx jubatus) is an endangered species with low fecundity and premature death in captivity. A previous survey determined that renal failure as a result of glomerulosclerosis was a major cause of death in captive populations. This study characterizes the morphologic, histochemical, and epidemiologic properties of glomerulosclerosis in this population. Kidneys from 87 cheetahs were examined by light microscopy; kidneys from six of those cheetahs were examined by electron and fluorescent microscopy using special stains specific for collagen, glycoproteins, reticulin, and fibrin. Immunohistochemistry for the advanced glycosylation end products (AGEs), pyrraline and pentosidine, also was performed on these cases. Glomerulosclerosis was present to some degree in 82% of the population, and in 30% of cheetahs the sclerosis was moderate to severe. Affected cheetah kidneys had thickened glomerular and tubular basement membranes, culminating in glomerulosclerosis. Thickened basement membranes were positive for collagen, glycoproteins, reticulin, and AGEs. Ultrastructurally, membrane material was homogeneous and fibrillar without electron-dense deposits. This glomerular lesion in cheetahs resembles diabetic glomerulopathy in humans and chronic progressive nephropathy in rats. No cheetahs had lesions of diabetes. However, adrenal cortical hyperplasia was prevalent and highly correlated with glomerulosclerosis in this population. If cheetahs with glomerulosclerosis had hypercorticoidism, then hyperglycemia and glomerular hypertension could lead to progressive AGE and plasma protein accumulations in membrane lesions. As in rats, daily feeding of high-protein diets and lack of genetic variation in the population may further contribute to the high prevalence of glomerulosclerosis in captive cheetahs.
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PMID:Glomerulosclerosis in captive cheetahs (Acinonyx jubatus). 992 51

Oxidative stress is apparent in pathology associated with aging and many age-related, chronic diseases, including atherosclerosis, diabetes mellitus, rheumatoid arthritis, and neurodegenerative diseases. Although it cannot be measured directly in biological systems, several biomarkers have been identified that provide a measure of oxidative damage to biomolecules. These include amino acid oxidation products (methionine sulfoxide, ortho-tyrosine (o-tyr) and dityrosine, chlorotyrosine and nitrotyrosine), as well as chemical modifications of protein following carbohydrate or lipid oxidation, such as N epsilon-(carboxymethyl)lysine and N epsilon-(carboxyethyl)lysine, and malondialdehyde and 4-hydroxynonenal adducts to amino acids. Other biomarkers include the amino acid cross-link pentosidine, the imidazolone adducts formed by reaction of 3-deoxyglucosone or methylglyoxal with arginine, and the imidazolium cross-links formed by the reaction of glyoxal and methylglyoxal with lysine residues in protein. These compounds have been measured in short-lived intracellular proteins, plasma proteins, long-lived extracellular proteins, and in urine, making them valuable tools for monitoring tissue-specific and systemic chemical and oxidative damage to proteins in biological systems. They are normally measured by sensitive high-performance liquid chromatography or gas chromatography-mass spectrometry methods, requiring both complex analytical instrumentation and derivatization procedures. However, sensitive immunohistochemical and ELISA assays are now available for many of these biomarkers. Immunochemical assays should facilitate studies on the role of oxidative stress in aging and chronic disease and simplify the evaluation of therapeutic approaches for limiting oxidative damage in tissues and treating pathologies associated with aging and disease. In this article we summarize recent data and conclusions based on immunohistochemical and ELISA assays, emphasizing the strengths and limitations of the techniques.
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PMID:Immunohistochemical and ELISA assays for biomarkers of oxidative stress in aging and disease. 992 37


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