Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dialysis-related amyloidosis (DRA) is a serious complication in long-term dialysis patients, and presents with carpal tunnel syndrome, cystic bone lesions, destructive spondylarthropathy, diffuse arthritis and periarthritis, systemic organ involvement, and dialysis-related spinal canal stenosis (DSCS). Recently a new concept of DSCS has been proposed that includes both destructive spondylarthropathy and myeloradiculopathy induced by extradural thickness. beta(2)-microglobulin (beta(2)M) amyloid was demonstrated to be modified with advanced glycation end products (AGEs) such as imidazolone, N(epsilon)-(carboxymethyl)lysine (CML), and pentosidine. Imidazolone is a reaction product of arginine residue in proteins with 3-deoxyglucosone (3-DG), which is markedly accumulated in uremic serum. Imidazolone is generated under nonoxidative conditions, while CML and pentosidine are formed by oxidative processes. Immunoelectron microscopy demonstrated that AGEs were localized not only in dialysis amyloid but also in nonamyloid collagenous structures, supporting the hypothesis that AGE modification of collagen might have pathogenic relevance in the deposition of beta(2)M on collagen. Serum levels of AGEs are increased in uremic patients. The dimeric form of beta(2)M in the dialysate and urine of uremic patients is more susceptible to imidazolone modification as observed in dialysis amyloid. However, the major component of dialysis amyloid is a native form of beta(2)M, while AGE-modified beta(2)M and truncated beta(2)M are the minor components. Thus I propose that 3-DG and the other dicarbonyl compounds accumulating in uremic serum promote the modification of beta(2)M with AGEs mainly after deposition of beta(2)M as amyloid. For the prevention and treatment of DRA, beta(2)M should be efficiently eliminated from circulating blood by kidney transplantation, hemodialysis, or hemodiafiltration using high-flux membranes and an adsorbent (Lixelle) column.
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PMID:Dialysis-related amyloidosis: pathogenesis focusing on AGE modification. 1126 80

Advanced glycation end products are a diverse class of posttranslational modifications, stemming from reactive aldehyde reactions, that have been implicated in the pathogenesis of a number of degenerative diseases. Because advanced glycation end products are accelerated by, and result in formation of, oxygen-derived free radicals, they represent an important component of the oxidative stress hypothesis of Alzheimer disease (AD). In this study, we used in situ techniques to assess N(epsilon)-(Carboxymethyl)lysine (CML), the predominant advanced glycation end product that accumulates in vivo, along with its glycation-specific precursor hexitol-lysine, in patients with AD as well as in young and aged-matched control cases. Both CML and hexitol-lysine were increased in neurons, especially those containing intracellular neurofibrillary pathology in cases of AD. The increase in hexitol-lysine and CML in AD suggests that glycation is an early event in disease pathogenesis. In addition, because CML can result from either lipid peroxidation or advanced glycation, while hexitol-lysine is solely a product of glycation, this study, together with studies demonstrating the presence of 4-hydroxy-2-nonenal adducts and pentosidine, provides evidence of two distinct oxidative processes acting in concert in AD neuropathology. Our findings support the notion that aldehyde-mediated modifications, together with oxyradical-mediated modifications, are critical pathogenic factors in AD.
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PMID:Active glycation in neurofibrillary pathology of Alzheimer disease: N(epsilon)-(carboxymethyl) lysine and hexitol-lysine. 1144 Aug 29

Previous studies from our laboratory demonstrated that N(epsilon)-(carboxymethyl)lysine (CML), one of the major advanced glycation end products (AGE), was accumulated in human pyramidal neurons in the hippocampus in an age-dependent manner. This suggests a potential link between AGE-accumulation and the aging process in neurons. The purpose of the present study was to examine whether this notion could be extended to other AGE structures, such as imidazolone and pentosidine. This was done using 19 human brains that were not affected by dementia. The immunohistochemical survey on distribution in brain tissues of imidazolone and pentosidine was carried out with monoclonal antibodies specific for imidazolone and pentosidine. A parallel control experiment was carried out with anti-CML antibody. The results showed that pentosidine and imidazolone were localized in neurons in different areas of human brain tissue, especially in neurons of CA4 in the hippocampus. The characteristic distribution of pentosidine and imidazolone is very similar to that of CML. Furthermore, when the accumulation of these AGE structures was compared with the age of individual brains it was found that accumulation of imidazolone, pentosidine and CML in the CA4 region increased with age. These findings taken together support the notion that the accumulation of AGE structures in the CA4 region might be closely related to the aging process in neurons.
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PMID:Accumulation of imidazolone, pentosidine and N(epsilon)-(carboxymethyl)lysine in hippocampal CA4 pyramidal neurons of aged human brain. 1240 85

Increasing evidence suggests an interaction of oxidative stress and the formation of advanced glycation end products (AGE) in the onset and progression of Alzheimer's disease. We studied levels of pentosidine and N(epsilon)-(carboxymethyl)-lysine (CML) in serum and cerebrospinal fluid (CSF) of 15 patients with probable Alzheimer's disease (AD), 20 patients with vascular dementia (VD), and 31 control subjects (14 matched for age, and 17 younger patients). AGE protein concentrations in CSF did not differ within controls when divided into two subgroups by age. We found significantly elevated levels of CML in CSF of AD patients and of pentosidine in CSF of patients suffering from vascular dementia when compared to controls. The concentrations of pentosidine and CML in serum apparently did not relate directly to CSF values, suggesting influence of extra-cerebral factors in serum samples. It is concluded that AGE proteins are differentially affected in these types of dementia, depending on the specific neuropathology. Furthermore, measurements of AGE products in vivo should rely on CSF rather than blood samples.
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PMID:Pentosidine and N(epsilon)-(carboxymethyl)-lysine in Alzheimer's disease and vascular dementia. 1249 67

We investigated whether serum levels of N-(carboxymethyl)lysine (CML), non-CML advanced glycation endproducts (AGEs), or pentosidine are associated with severity of diabetic microvascular complications in patients with Type 1 diabetes. Serum levels of CML, non-CML AGE, and pentosidine were measured by an enzyme-linked immunosorbent assay in 38 males and 47 females aged 31+/-8 years (mean+/-S.D.) with Type 1 diabetes for 18.7+/-7.0 years. There was a significant correlation between serum levels of CML or non-CML AGE and current HbA(1c) level (P<.01 and P<.05, respectively). The serum levels of non-CML AGE, but not CML or pentosidine, were significantly increased as normal renal status advanced to microalbuminuria, clinical nephropathy, and hemodialysis (P<.0001) and were positively correlated with urinary albumin excretion (UAE) in patients with Type 1 diabetes (P<.0001). A significant elevation of serum non-CML AGE was found in association with the severity of diabetic retinopathy (P<.0001). We found in the present study that CML levels were also increased in the stage of simple retinopathy, the early stage of clinically evident retinopathy (P<.05). Serum levels of non-CML AGE were significantly associated with the severity of diabetic nephropathy and retinopathy, suggesting a role of non-CML AGE in the progression of microvascular complications in patients with Type 1 diabetes. Since serum levels of CML were significantly increased in patients with simple retinopathy, CML may participate in the initiation of diabetic retinopathy.
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PMID:Serum levels of non-carboxymethyllysine advanced glycation endproducts are correlated to severity of microvascular complications in patients with Type 1 diabetes. 1250 51

Non-enzymatic glycoxydation and lipoxidation of proteins continues to stimulate great interest in gerontology as both markers and promoters of aging. The first aim of the study was to determine the age-related changes in levels of Nepsilon-(carboxymethyl)lysine (CML) and 4-hydroxy-2-nonenal (HNE) present on proteins of the cardiovascular system of Fischer 344 rats and identify the particular polypeptides being modified. The second objective was to evaluate whether pharmacological administration of aminoguanidine (1g/L in the drinking water) could reverse protein glycoxidation and lipoxidation. CML content in serum, aorta, and heart proteins from 28-month-old rats was double of that found in 4-month-old animals. AG administration to old rats for 3 months from the age of 25 months lowered CML content by 15 (P=.2275), 44 (P<.0001), and 28% (P=.0072) in serum, aorta, and heart, respectively. Serum albumin, transferrin and immunoglobulins were most prominently adducted by both CML and HNE. While the extent of albumin and transferrin modification was comparable between age groups, CML and HNE bound to immunoglobulins increased in the sera of old rats as a result of the accumulation of immunoglobulin heavy and light chains. AG treatment prevented immunoglobulin accumulation in serum, suggesting a beneficial action on renal filtration. Lipoxidation of heart mitochondrial proteins was prevalent over glycoxidation, either as CML or pentosidine. Although AG prevented HNE-induced inactivation of the alpha-ketoglutarate dehydrogenase complex in vitro, it had no effect in rat hearts, suggesting AG could not reach the mitochondrial matrix.
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PMID:Reversal by aminoguanidine of the age-related increase in glycoxidation and lipoxidation in the cardiovascular system of Fischer 344 rats. 1558 11

The levels of plasma 3-deoxyglucosone (3-DG) increase under hyperglycemic conditions and are associated with the pathogenesis of diabetic complications because of the high reactivity of 3-DG with proteins to form advanced glycation end products (AGE). To investigate potential markers for 3-DG-mediated protein modification in vitro and in vivo, we compared the yield of several 3-DG-derived AGE structures by immunochemical analysis and HPLC and measured their localization in human atherosclerotic lesions. When BSA was incubated with 3-DG at 37 degrees C for up to 4 wk, the amounts of N(epsilon)-(carboxymethyl)lysine (CML) and 3-DG-imidazolone steeply increased with incubation time, whereas the levels of pyrraline and pentosidine increased slightly by day 28. In contrast, significant amounts of pyrraline and pentosidine were also observed when BSA was incubated with 3-DG at 60 degrees C to enhance AGE-formation. In atherosclerotic lesions, CML and 3-DG-imidazolone were found intracellularly in the cytoplasm of most foam cells and extracellularly in the atheromatous core. A weak-positive immunoreaction with pyrraline was found in the extracellular matrix and a few foam cells in aortic intima with atherosclerotic lesions. Our results provide the first evidence that CML and 3-DG-imidazolone are major AGE structures in 3-DG-modified proteins, and that 3-DG-imidazolone provides a better marker for protein modification by 3-DG than pyrraline.
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PMID:Nepsilon-(Carboxymethyl)lysine and 3-DG-imidazolone are major AGE structures in protein modification by 3-deoxyglucosone. 1559 92

The involvement of radical stress has been suggested as a cause for complications in patients on dialysis, such as arteriosclerosis, dialysis-related amyloidosis, etc. It has been reported that the increase in radical stress is not only seen in renal failure, but that its amplified effect is also seen in the process of blood purification. Our group has reported on the radical stress-reducing effect of HDF. We performed four types of blood purification (HD; on-line HDF; pre, on-line HDF; post, P/P HDF) in patients on maintenance dialysis using the polysulfone (APS) dialyzer. The change in radical related markers such as pentosidine (total, free) and CML (total, free), and the CTL/Cr ratio, and the hydroperoxide radicals were studied. In HDF (post, pre), the amplification rate of hydroperoxide radicals was significantly low, whereas the reduction rate of CTL/Cr ratio as index for hydroxy radicals was significantly higher in on-line HDF than in HD. Both the total CML and T-pentosidine increased in HD but showed a decrease in HDF. As HDF uses large amounts of replacement solution, the following effects can be expected: (a) suppression of the amplification of hydroperoxide radicals and suppression of the amplification of hydroxy radicals, and (b) suppression of fat oxidation by AGEs themselves. These antiradical stress effects are presumed to be exerted by effective removal of radical carrier protein, denatured protein, and complement protein in HDF, by dilution of radicals by massive use of replacement solution, and by the sequential reduction of the excitation and amplification effects.
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PMID:Effect of hemodiafiltration against radical stress in the course of blood purification. 1565 28

Incomplete digestion of advanced glycation end product (AGE)-modified protein results in the formation of low-molecular weight degradation products incorporating AGE modifications (LMW-AGEs). In addition to being biomarkers of AGE modification, LMW-AGEs may have a high toxic potential, being free to interact with AGE receptors at distant sites via the circulation. Several free AGEs have been identified, including pentosidine, N(epsilon)-(carboxymethyl)lysine (CML), and free-imidazole AGEs. In addition, fluorescence (370 nm [excitation]/440 nm [emission]) in the LMW phase of serum correlates with tissue fluorescence, an established marker for AGE modification. In experimental diabetes, LMW fluorescence increases with duration of disease and is normalized with the AGE inhibitor aminoguanidine. LMW fluorescence is also higher in patients with diabetes, in whom it is associated with glomerular filtration rate and hemoglobin. Patients with hyperfiltration have lower LMW fluorescence than those with normal renal function, which may protect them from AGE accumulation in the short term. These findings provide clinical support for the association between AGEs and progressive renal injury in diabetes.
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PMID:Low-molecular weight advanced glycation end products: markers of tissue AGE accumulation and more? 1603 88

Several lines of evidence suggest that both advanced glycation end products (AGEs) and oxidation processes play key roles in the physiology of aging and age-related pathologies, leading to irreversible proteins modifications in both tissues and the extracellular matrix. Such an accelerated accumulation of these modifications has been reported to be present in several age-related chronic diseases, such as atherosclerosis, diabetes, arthritis, and neurodegenerative diseases. The current literature reveals that the specific inhibition of AGEs may constitute an innovative therapeutic goal. In experimental animals, the use of sartans significantly reduces blood pressure and kidney pentosidine content, improving both histologic renal damage and proteinuria. In this study, 12 subjects who were affected by diabetes mellitus and hypertension were subjected to oral antihypertensive therapy with valsartan (class of sartans) with timed sampling of plasma and urine pentosidine, N(epsilon)-(carboxymethyl)lysine (CML), malondialdehyde, and isoprostanes levels, respectively, at baseline and after both 3 and 6 months, with parallel ongoing evaluation of glycemic control and blood pressure levels. Valsartan elicited a good antihypertensive effect with a 30% decrease in plasma pentosidine levels (P < .05) after 3 months of therapy, followed by a slight increase after 6 months. Urinary pentosidine concentrations exhibited a 40% decrease after 3 months (215 +/- 19 vs 129 +/- 23 nmol/24 h) and a further significant reduction after 6 months of therapy (105 +/- 24 nmol/24 h). Plasma CML levels showed a progressive decrease after 3 months (23.15 +/- 3.215 vs 19.88 +/- 1.684 micromol/mL) and achieved a further slight reduction after 6 months of therapy (19.48 +/- 1.339 micromol/mL); for urinary CML, a statistically significant reduction was gained after the sixth month of therapy (48.51 +/- 5.70 vs 30.30 +/- 2.77 micromol/24 h after 3 months and 27.02 +/- 4.13 micromol/24 h after 6 months; F = 7.62, P < .005). Plasma and urinary concentrations of malondialdehyde were slightly modified by valsartan treatment; the mean levels after both 3 and 6 months did not significantly differ from baseline. Urinary 15-F2t-isoprostanes (2.96 +/- 0.45 ng/24 h) levels displayed a progressive decrease after both 3 (2.27 +/- 0.31 ng/24 h) and 6 months (1.70 +/- 0.23 ng/24 h) with statistical significance achieved only at the end of the study (P < .05). The present data suggest interesting in vivo antiglycation and antioxidation effects of this angiotensin II receptor antagonist with reductions in plasma and urinary pentosidine, plasma CML, and urinary isoprostanes levels. The present study supports an antagonistic role of valsartan in the production of AGEs precursors through the chelation of transition metals and an antioxidant activity that scavenges reactive oxygen species. This property of valsartan may broaden the scope of newly developed pharmacologic inhibitors of advanced glycoxidation.
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PMID:Effects of valsartan therapy on protein glycoxidation. 1714 34


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