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Seikoh Horiuchi - One of the best experts on this subject based on the ideXlab platform.
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ne carboxymethyl lysine and 3 dg Imidazolone are major age structures in protein modification by 3 deoxyglucosone
Journal of Biochemistry, 2004Co-Authors: Tadashi Jono, Paul J Thornalley, Naila Ahmed, Motohiro Takeya, Ryoji Nagai, Seikoh HoriuchiAbstract: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 advancedglycation 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°C for up to 4 wk, the amounts of N e -(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, significants amount of pyrraline and pentosidine were also observed when BSA was incubated with 3-DG at 60°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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ne carboxymethyl lysine and 3 dg Imidazolone are major age structures in protein modification by 3 deoxyglucosone
Journal of Biochemistry, 2004Co-Authors: Tadashi Jono, Paul J Thornalley, Naila Ahmed, Motohiro Takeya, Ryoji Nagai, Xia Lin, Seikoh HoriuchiAbstract: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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detection of 3 deoxyglucosone derived age structures in vitro
International Congress Series, 2002Co-Authors: Tadashi Jono, Kiminori Miyazaki, Toshinori Kitamura, Paul J Thornalley, Naila Ahmed, Ryoji Nagai, Seikoh HoriuchiAbstract:Abstract In the Maillard reaction, 3-deoxyglucosone (3-DG) was known to generate from Amadori product and contribute to further AGE formation such as I a -(carboxymethyl)lysine (CML), 3-DG-derived Imidazolone (3-DG-Imidazolone) and pyrraline. However, main AGE structures generated from 3-DG modification have not yet been elucidated. To solve this issue, we set up the detection system for AGE by immunochemical analysis as well as high-performance liquid chromatography (HPLC) and determined them in 3-DG-modified bovine serum albumin (BSA). When BSA was incubated at 37 °C for up to 4 weeks with 3-DG, the reactivity of antibodies against CML and 3-DG-Imidazolone increased steeply with incubation time, whereas the reactivity of antibodies against pyrraline was increased slightly. In contrast, in addition to CML and 3-DG-Imidazolone, significant amount of pyrraline was observed when AGE formation was enhanced by high temperature at 60 °C. In HPLC analysis, CML (1.10 mol/mol of BSA), 3-DG-Imidazolone (0.84 mol/mol of BSA) and pyrraline (0.33 mol/mol of BSA) were detected in BSA incubated with 3-DG at 37 °C for 4 weeks. Taken together, our analyses clarified that formation of CML and 3-DG-Imidazolone is higher than that of pyrraline during the incubation of protein with 3-DG.
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accumulation of Imidazolone pentosidine and n epsilon carboxymethyl lysine in hippocampal ca4 pyramidal neurons of aged human brain
Pathology International, 2002Co-Authors: Tadashi Jono, Kiminori Miyazaki, Toshinori Kitamura, Ryoji Nagai, Takemi Kimura, Junichi Takamatsu, Takefumi Yuzuriha, Seikoh HoriuchiAbstract: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.
Toshimitsu Niwa - One of the best experts on this subject based on the ideXlab platform.
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accumulation of renin and Imidazolone in peritubular capillary endothelial cells in insulin resistant hypertensive rats
Journal of Nephrology, 2011Co-Authors: Zoltan Wagner, Peter Degrell, Gergo A Molnar, Lajos Marko, Toshimitsu Niwa, Balázs Lukáts, Zoltán Karádi, Istvan WittmannAbstract:Background: Peritubular endothelium plays a key role in the development and progression of diabetic and nondiabetic chronic kidney disease. Renal injury in disorders of glucose metabolism may appear as early as in the stage of impaired glucose tolerance (IGT) and is accelerated by hypertension. The aim of our study was to investigate renal histology in rats with hyper- tension and IGT, with special emphasis on the peritu- bular endothelium. Methods: Hypertension and IGT (H/IGT) were provoked in adult male Wistar rats by bilateral administration of methylglyoxal into the ventromedial hypothalamus. Immunohistochemistry with anti-renin and anti-imi- dazolone antibodies and immunoelectron microscopy with anti-renin antibody were performed. Results: H/IGT rats showed tubulointerstitial fibrosis as well as renin and Imidazolone staining in the papil- lary region. The patterns of immunostaining for renin and Imidazolone were similar to that of endothelium. On electron microscopy, peritubular capillary endothe- lial cells and to a less extent, tubular epithelial cells showed renin positivity. Discussion: Impaired glucose tolerance complicated with hypertension leads to tubulointerstitial fibrosis in rat kidney. Imidazolone deposition and renin produc- tion in peritubular capillary endothelial cells may play a role in the development of tubulointerstitial fibrosis.
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3 deoxyglucosone and ages in uremic complications inactivation of glutathione peroxidase by 3 deoxyglucosone
Kidney International, 2001Co-Authors: Toshimitsu Niwa, Saori TsukudhiAbstract:3-Deoxyglucosone and AGEs in uremic complications: Inactivation of glutathione peroxidase by 3-deoxyglucosone. 3-Deoxyglucosone (3-DG) is accumulated not only in uremic serum but also in uremic erythrocytes. 3-DG rapidly reacts with protein amino groups to form advanced glycation end products (AGEs) such as Imidazolone, pyrraline, and Ne-(carboxymethyl)lysine, among which Imidazolone is the AGE that is most specific for 3-DG. In diabetes, hyperglycemia enhances the synthesis of 3-DG via the Maillard reaction and the polyol pathway and thereby leads to its high plasma and erythrocyte levels. In uremia, however, the decreased catabolism of 3-DG that may be due to the loss of 3-DG reductase activity in the end-stage kidneys may lead to a high plasma 3-DG level. The elevated 3-DG levels in uremic patients may promote the formation of AGEs such as Imidazolone in erythrocytes, aortas, and dialysis-related amyloid deposits. Treatment with an aldose reductase inhibitor reduced the erythrocyte levels of 3-DG and AGEs such as Imidazolone in diabetic uremic patients. This finding demonstrates an important role of the polyol pathway in the formation of erythrocyte 3-DG and AGEs. The erythrocyte levels of 3-DG are elevated in not only diabetic uremic but also nondiabetic uremic patients. 3-DG showed some cytotoxicities by inducing intracellular oxidative stress. In contrast, oxidative stress was demonstrated to cause accumulation of intracellular 3-DG. Recently, we have demonstrated that 3-DG inactivates intracellular enzymes such as glutathione peroxidase, a key enzyme in the detoxification of hydrogen peroxide. Thus, intracellular accumulation of 3-DG may enhance oxidative stress by inactivating the antioxidant enzymes. In conclusion, 3-DG may play a principal role in the development of uremic complications, such as dialysis-related amyloidosis, atherosclerosis, and enhanced oxidative stress.
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3 deoxyglucosone metabolism analysis biological activity and clinical implication
Journal of Chromatography B: Biomedical Sciences and Applications, 1999Co-Authors: Toshimitsu NiwaAbstract:3-Deoxyglucosone (3-DG) is synthesized via the Maillard reaction and the polyol pathway, and is detoxified to 3-deoxyfructose and 2-keto-3-deoxygluconic acid. 3-DG rapidly reacts with protein amino groups to form advanced glycation end products (AGEs) such as Imidazolone, pyrraline, N e -(carboxymethyl)lysine and pentosidine, among which Imidazolone is the AGE most specific for 3-DG. As demonstrated by using gas chromatography-mass spectrometry or high-performance liquid chromatography, plasma 3-DG levels are markedly increased in diabetes and uremia. Although the plasma 3-DG levels had been controversial, it was clearly demonstrated that its plasma level depends on the deproteinization method by which either free or total 3-DG, presumably bound to proteins, is measured. In diabetes, hyperglycemia enhances the synthesis of 3-DG via the Maillard reaction and the polyol pathway, and thereby leads to its high plasma and erythrocyte levels. In uremia, however, the decreased catabolism of 3-DG, which may be due to the loss of 3-DG reductase activity in the end-stage kidneys, may lead to high plasma 3-DG level. The elevated 3-DG levels in plasma and erythrocytes may promote the formation of AGEs such as Imidazolone, as demonstrated by immunohistochemistry and immunochemistry using an anti-Imidazolone antibody. Although AGE-modified proteins prepared in vitro exhibit a variety of biological activities, known AGE structures have not yet been demonstrated to show any biological activities. Because 3-DG is potent in the formation of AGEs and has some biological activities, such as cellular toxicity, it may be more important in the development of diabetic and uremic complications than the known AGE structures. By demonstrating that treatment with an aldose reductase inhibitor reduces the erythrocyte levels of 3-DG and AGEs, such as Imidazolone, light is shed on the mystery of how aldose reductase inhibitors may prove beneficial in diabetic complications. These evidences suggest that 3-DG plays a principal role in the development of diabetic and uremic complications.
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Imidazolone a novel advanced glycation end product is present at high levels in kidneys of rats with streptozotocin induced diabetes
FEBS Letters, 1997Co-Authors: Toshimitsu Niwa, Yayoi Ishizaki, Tomoyuki Katsuzaki, Noriyuki Tatemichi, Fumitaka Hayase, Takashi Miyazaki, Toshihiko Uematsu, Yoshifumi TakeiAbstract:We produced a monoclonal antibody to Imidazolones A and B, novel advanced glycation end products formed from the reaction of 3-deoxyglucosone (3-DG) with the guanidino group of arginine. Liquid chromatography/mass spectrometry demonstrated that the formation of Imidazolone A by incubating 3-DG with arginine is very rapid, reaching a maximum concentration within 24 h, but the formation of Imidazolone B is very slow and low in quantity even after 2 weeks. Thus, at physiological conditions the formation of Imidazolone A is dominant, while that of Imidazolone B is negligible. Immunochemistry demonstrated that the Imidazolone content in the kidneys of streptozotocin-induced diabetic rats was significantly higher than in the control rats. Serum levels of 3-DG in the diabetic rats were also significantly higher than in control rats. 3-DG attacks the arginine residues of the tissue proteins, producing Imidazolone at high levels in the kidneys affected by diabetic nephropathy.
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Immunohistochemical detection of Imidazolone, a novel advanced glycation end product, in kidneys and aortas of diabetic patients
Journal of Clinical Investigation, 1997Co-Authors: Toshimitsu Niwa, Yayoi Ishizaki, Tomoyuki Katsuzaki, Noriyuki Tatemichi, Fumitaka Hayase, Shigeru Miyazaki, Takashi Miyazaki, Yoshifumi TakeiAbstract:To investigate the role of the Maillard reaction in the pathogenesis of diabetic complications, we produced several clones of monoclonal antibodies against advanced glycation end products (AGEs) by immunizing mice with AGE-modified keyhole limpet hemocyanin, and found that one clone (AG-1) of the anti-AGE antibodies reacted specifically with Imidazolones A and B, novel AGEs. Thus, the Imidazolones, which are the reaction products of the guanidino group of arginine with 3-deoxyglucosone (3-DG), a reactive intermediate of the Maillard reaction, were found to be common epitopes of AGE-modified proteins produced in vitro. We determined the erythrocyte levels of Imidazolone in diabetic patients using ELISA with the monoclonal anti-Imidazolone antibody. The Imidazolone levels in the erythrocytes of diabetic patients were found to be significantly increased as compared with those of healthy subjects. Then we studied the localization of Imidazolone in the kidneys and aortas obtained from diabetic patients by immunohistochemistry using the antibody. Specific Imidazolone immunoreactivity was detected in nodular lesions and expanded mesangial matrix of glomeruli, and renal arteries in an advanced stage of diabetic nephropathy, as well as in atherosclerotic lesions of aortas. This study first demonstrates the localization of Imidazolone in the characteristic lesions of diabetic nephropathy and atherosclerosis. These results, taken together with a recent demonstration of increased serum 3-DG levels in diabetes, strongly suggest that Imidazolone produced by 3-DG may contribute to the progression of long-term diabetic complications such as nephropathy and atherosclerosis.
Tadashi Jono - One of the best experts on this subject based on the ideXlab platform.
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ne carboxymethyl lysine and 3 dg Imidazolone are major age structures in protein modification by 3 deoxyglucosone
Journal of Biochemistry, 2004Co-Authors: Tadashi Jono, Paul J Thornalley, Naila Ahmed, Motohiro Takeya, Ryoji Nagai, Seikoh HoriuchiAbstract: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 advancedglycation 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°C for up to 4 wk, the amounts of N e -(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, significants amount of pyrraline and pentosidine were also observed when BSA was incubated with 3-DG at 60°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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ne carboxymethyl lysine and 3 dg Imidazolone are major age structures in protein modification by 3 deoxyglucosone
Journal of Biochemistry, 2004Co-Authors: Tadashi Jono, Paul J Thornalley, Naila Ahmed, Motohiro Takeya, Ryoji Nagai, Xia Lin, Seikoh HoriuchiAbstract: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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detection of 3 deoxyglucosone derived age structures in vitro
International Congress Series, 2002Co-Authors: Tadashi Jono, Kiminori Miyazaki, Toshinori Kitamura, Paul J Thornalley, Naila Ahmed, Ryoji Nagai, Seikoh HoriuchiAbstract:Abstract In the Maillard reaction, 3-deoxyglucosone (3-DG) was known to generate from Amadori product and contribute to further AGE formation such as I a -(carboxymethyl)lysine (CML), 3-DG-derived Imidazolone (3-DG-Imidazolone) and pyrraline. However, main AGE structures generated from 3-DG modification have not yet been elucidated. To solve this issue, we set up the detection system for AGE by immunochemical analysis as well as high-performance liquid chromatography (HPLC) and determined them in 3-DG-modified bovine serum albumin (BSA). When BSA was incubated at 37 °C for up to 4 weeks with 3-DG, the reactivity of antibodies against CML and 3-DG-Imidazolone increased steeply with incubation time, whereas the reactivity of antibodies against pyrraline was increased slightly. In contrast, in addition to CML and 3-DG-Imidazolone, significant amount of pyrraline was observed when AGE formation was enhanced by high temperature at 60 °C. In HPLC analysis, CML (1.10 mol/mol of BSA), 3-DG-Imidazolone (0.84 mol/mol of BSA) and pyrraline (0.33 mol/mol of BSA) were detected in BSA incubated with 3-DG at 37 °C for 4 weeks. Taken together, our analyses clarified that formation of CML and 3-DG-Imidazolone is higher than that of pyrraline during the incubation of protein with 3-DG.
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accumulation of Imidazolone pentosidine and n epsilon carboxymethyl lysine in hippocampal ca4 pyramidal neurons of aged human brain
Pathology International, 2002Co-Authors: Tadashi Jono, Kiminori Miyazaki, Toshinori Kitamura, Ryoji Nagai, Takemi Kimura, Junichi Takamatsu, Takefumi Yuzuriha, Seikoh HoriuchiAbstract: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.
Shklyaev Y.v. - One of the best experts on this subject based on the ideXlab platform.
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Structure of the iron(III) chloride complex with 2-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolylidene-1)-5,5-dimethyl-2,3,5,6-tetrahydroimidazo[2.1-a]isoquinolin-3-one
IAPC Nauka Interperiodica, 2020Co-Authors: Sokol V.i., Davydov V.v., Merkur'eva N.y., Sergienko V.s., Pervushina S.a., Shklyaev Y.v.Abstract:The iron(III) complex with 2-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolylidene-1)-5,5-dimethyl-2,3,5,6-tetrahydroimidazo[2.1-a]isoquinolin-3-one (L) was studied by X-ray diffraction. The complex (LH) . [FeCl4] . C3H6O has a cation-anion structure. The proton in the HL+ cation is located at the N(2) nitrogen atom in position 1 of the Imidazolone fragment. The cation contains a hydrogen bond (O(1)-H(1), 1.31(5) Angstrom; N(3)-H(1), 1.37(5) Angstrom; O(1)...N(3), 2.67 Angstrom; O(1)H(1)N(3), 167(4)degrees) in which the position of the H(1) atom corresponds to the average of two equiprobable half-populated positions at the O(1) and N(3) atoms. The pi-electron density in the Imidazolone moiety is delocalized. The C-C bond length between the Imidazolone and dihydroisoquinoline moieties (1.42(1) Angstrom) is much greater than the standard C=C double bond length. The FeCl4- anion has a usual geometry
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Crystal structure of the iron(III) chloride complex with 2-(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolylidene-1)-5,5-dimethyl-2,3,5, 6-tetrahydroimidazo[2.1-a]isoquinolin-3-one
IAPC Nauka Interperiodica, 2020Co-Authors: Sokol V.i., Davydov V.v., Sergienko V.s., Pervushina S.a., Shklyaev Y.v.Abstract:The iron(III) complex with 2-(3,3-dimethyl-1,2,3,4- tetrahydroisoquinolylidene-1)-5,5-dimethyl-2,3,5,6-tetrahydroimidazo[2.1-a] isoquinolin-3-one (L) was studied by X-ray diffraction. The complex (LH)· [FeCl4]·C3H6O has a cation-anion structure. The proton in the HL+ cation is located at the N(2) nitrogen atom in position 1 of the Imidazolone fragment. The cation contains a hydrogen bond (O(1)-H(1), 1.31(5) Å; N(3)-H(1), 1.37(5) Å; O(1)⋯N(3), 2.67 Å; O(1)H(1)N(3), 167(4)°) in which the position of the H(1) atom corresponds to the average of two equiprobable half-populated positions at the O(1) and N(3) atoms. The π-electron density in the Imidazolone moiety is delocalized. The C-C bond length between the Imidazolone and dihydroisoquinoline moieties (1.42(1) Å) is much greater than the standard C=C double bond length. The FeCl4 - anion has a usual geometry
Paul J Thornalley - One of the best experts on this subject based on the ideXlab platform.
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ne carboxymethyl lysine and 3 dg Imidazolone are major age structures in protein modification by 3 deoxyglucosone
Journal of Biochemistry, 2004Co-Authors: Tadashi Jono, Paul J Thornalley, Naila Ahmed, Motohiro Takeya, Ryoji Nagai, Seikoh HoriuchiAbstract: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 advancedglycation 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°C for up to 4 wk, the amounts of N e -(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, significants amount of pyrraline and pentosidine were also observed when BSA was incubated with 3-DG at 60°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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ne carboxymethyl lysine and 3 dg Imidazolone are major age structures in protein modification by 3 deoxyglucosone
Journal of Biochemistry, 2004Co-Authors: Tadashi Jono, Paul J Thornalley, Naila Ahmed, Motohiro Takeya, Ryoji Nagai, Xia Lin, Seikoh HoriuchiAbstract: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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detection of 3 deoxyglucosone derived age structures in vitro
International Congress Series, 2002Co-Authors: Tadashi Jono, Kiminori Miyazaki, Toshinori Kitamura, Paul J Thornalley, Naila Ahmed, Ryoji Nagai, Seikoh HoriuchiAbstract:Abstract In the Maillard reaction, 3-deoxyglucosone (3-DG) was known to generate from Amadori product and contribute to further AGE formation such as I a -(carboxymethyl)lysine (CML), 3-DG-derived Imidazolone (3-DG-Imidazolone) and pyrraline. However, main AGE structures generated from 3-DG modification have not yet been elucidated. To solve this issue, we set up the detection system for AGE by immunochemical analysis as well as high-performance liquid chromatography (HPLC) and determined them in 3-DG-modified bovine serum albumin (BSA). When BSA was incubated at 37 °C for up to 4 weeks with 3-DG, the reactivity of antibodies against CML and 3-DG-Imidazolone increased steeply with incubation time, whereas the reactivity of antibodies against pyrraline was increased slightly. In contrast, in addition to CML and 3-DG-Imidazolone, significant amount of pyrraline was observed when AGE formation was enhanced by high temperature at 60 °C. In HPLC analysis, CML (1.10 mol/mol of BSA), 3-DG-Imidazolone (0.84 mol/mol of BSA) and pyrraline (0.33 mol/mol of BSA) were detected in BSA incubated with 3-DG at 37 °C for 4 weeks. Taken together, our analyses clarified that formation of CML and 3-DG-Imidazolone is higher than that of pyrraline during the incubation of protein with 3-DG.
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molecular characteristics of methylglyoxal modified bovine and human serum albumins comparison with glucose derived advanced glycation endproduct modified serum albumins
Journal of Protein Chemistry, 1995Co-Authors: Marie E Westwood, Paul J ThornalleyAbstract:The amino acid modification, gel filtration chromatographic, and electrophoretic characteristics of bovine and human serum albumins irreversibly modified by methylglyoxal (MG-SA) and by glucose-derived advanced glycation endproducts (AGE-SA) were investigated. Methylglyoxal selectively modified arginine residues at low concentration (1 mM); at high methylglyoxal concentration (100 mM), the extent of arginine modification increased and lysine residues were also modified. Both arginine and lysine residues were modified in AGE-SA. Analytical gel filtration HPLC of serum albumin derivatives suggested that the proportion of dimers and oligomers increased with modification in both low and highly modified MG-SA and AGE-SA derivatives relative to unmodified serum albumins. In SDS-PAGE analysis, dimers and oligomers of low-modified MG-SA were dissociated into monomers, but not in highly modified MG-SA. MG-SA had increased anodic electrophoretic mobility under nondenaturing conditions at pH 8.6, indicating an increased net negative charge, which increased with extent of modification; highly modified MG-SA and AGE-SA had similar high electrophoretic mobilities. MG-SA derivatives were fluorescent: the fluorescence was characteristic of the arginine-derived Imidazolone N delta-(5-methyl-4-imidazolon-2-yl)ornithine, but other fluorophores were also present. AGE-SA had similar fluorescence, attributed, in part, to glucose-derived Imidazolones. AGE formed from glucose-modified proteins and AGE-like compounds formed from methylglyoxal-modified proteins may both be signals for recognition and degradation of senescent macromolecules.
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binding and modification of proteins by methylglyoxal under physiological conditions a kinetic and mechanistic study with n alpha acetylarginine n alpha acetylcysteine and n alpha acetyllysine and bovine serum albumin
Journal of Biological Chemistry, 1994Co-Authors: Marie E Westwood, Antony C Mclellan, Trevor Selwood, Paul J ThornalleyAbstract:The physiological alpha-oxoaldehyde methylglyoxal binds and modifies arginine, lysine, and cysteine residues in proteins. The kinetics and mechanism of these reactions were investigated with N alpha-acetylamino acids and bovine serum albumin at pH 7.4 and 37 degrees C. The reaction of methylglyoxal with N alpha-acetylarginine involved the initial reversible formation of glycosylamine and 4,5-dihydroxy-5-methylimidazolidine derivatives, with further slow irreversible conversion to an Imidazolone, N alpha-acetyl-N delta- (5-methyl-4-imidazolon-2-yl)ornithine. The Imidazolone was fluorescent with an excitation lambda max value of 320 nm and an emission lambda max value of 398 nm. Methylglyoxal reacted reversibly with N alpha-acetyllysine to form glycosylamine and bisglycosylamine derivatives. Further reaction of these glycosylamines occurred to form brown, fluorescent oligomers that were not characterized. Methylglyoxal reacted rapidly and reversibly with N alpha-acetylcysteine to form the hemithioacetal adduct. The reaction of methylglyoxal with bovine serum albumin (BSA) at pH 7.4 and 37 degrees C involved the reversible and irreversible formation of methylglyoxal-BSA adducts. Irreversible modification of BSA occurred mainly on arginine residues to form Imidazolone. The formation of methylglyoxal-modified proteins involves glycoxidation leading to advanced glycation end product-like fluorescence. It is expected to be increased in diabetes mellitus and may be linked to the development of diabetic complications.