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Detemination of The Main Advanced Glycation End Product of The Maillard Reaction and Its Significance as A Biochemical Marker for Diabetic Complications

Research Project

Project/Area Number 07557076
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section試験
Research Field 内分泌・代謝学
Research InstitutionKumamoto University

Principal Investigator

HORIUCHI Seikoh  Kumamoto University School of Medicine Professor, 医学部, 教授 (10117377)

Co-Investigator(Kenkyū-buntansha) IENAGA Kazuharu  Institution, Institute of Bio-Active Science, Nippon Zoki Pharmaceutical Co.Ltd., 生物活性科学研究所, 部長
MAEDA Kenji  Institution, Department of Internal Medicine, The Branch Hospital, Nagoya Univer, 医学部, 教授 (90023853)
Project Period (FY) 1995 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥14,500,000 (Direct Cost: ¥14,500,000)
Fiscal Year 1996: ¥5,100,000 (Direct Cost: ¥5,100,000)
Fiscal Year 1995: ¥9,400,000 (Direct Cost: ¥9,400,000)
Keywordsadvanced glycation end products (AGE) / main AGE-structure / fluorescence / crosslinking / posttranslational protein modification / diabetic complications / aging / 後期反応生成物(AGE) / 主要AGE構造体 / 主要蛍光物質 / 抗AGE特異抗体
Research Abstract

Incubation of glucose with proteins in vitro results in formation of early-products such as Schiff base and Amadori product. Upon further incubations, these early-products leads to formation of advanced glycation end products (AGE) which are characterized by fluorescence, brown color and intra-and intermolecular crosslinking. Recent immunological studies using anti-AGE antibody suggest a potential role of AGE-modification in aging and age-enhanced disease processes such as atherosclerosis and diabetic complications. To solve this suggestion, a main AGE-structure (s) expressed in vivo is to be determined. In the present study, we isolated the main AGE-structure from AGE-lysine derivative and determined its chemical structure.
The following results were obtained by two-years projects.
[1] The AGE-sample was obtained after long-term incubation of alpha-tosyl-lysine-methyl ester with glucose and the main fluorescent compound named as X1 was purified from this sample. Chemical analyzes by mass spectroscopy and 1H-NMR and 13C-NMR successfully identified its structure as 1,7-disubstituted-5- (1,2,3,4-tetrahydroxybutyl) -1,4-dihydro-4-oxo-1,7-naphthyridinium cation, indicating two lysine residues are crosslinked by pyridinium structure derived from two glucose molecules.
[2] Immunological studies using the rabbit polyclonal anti-X1 antibody demonstrated the presence of X1 in (i) human lens proteins, (ii) foam cells as well as in extracellular spaces in human atherosclerotic lesions, (iii) glomerulus and renal tubules of diabetic nephropathy, (iv) in Carpal tunnel deposits (beta2-microglobulin) of dialysis-related amyloidosis, (v) elastin fibers of skin dermis in actinic elastosis. These results indicate that X1, one of the main AGE-structures in vivo, plays an important role in aging and/or age-enhanced disease processes such as diabetic complications and atherosclerosis of vascular walls.

Report

(3 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • Research Products

    (44 results)

All Other

All Publications (44 results)

  • [Publications] Araki,N.: "Macrophage scavenger receptor mediates the endocytic uptake of advanced glycation end-products of the Maillard reaction" Eur.J.Biochem.230. 408-415 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kume,S.: "Immunohistrochemical and ultrastrucutral detection of advanced a glycation end products in altherosclerotic lesions of human aorta using a novel specific monoclonal antibody" Am.J.Pathol.147. 654-667 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Makino,H.: "Ultrastructure of nonenzymatically glycated mesangial matrix in diabetic nephrophathy" Kidney International,. 48. 517-526 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Saishoji,T.: "Advanced glycation end products stimulate plasminogen activator activity via GM-CSF in RAW264.7 cells" Biochem.Biophys.Res.Commun.217. 278-285 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Miyata,T.: "Identification of pentosidine as a native structure for advanced glycation end products in b2-microglobulin forming amyloid fibrils in patients with dialysis-related amyloidosis" Proc,Natl.Acad.Sci.USA.93. 2353-2358 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Meng,J.: "Advanced glycation end-products of the Maillard reaction in aortic pepsin-insoluble collagen from diabetic rats." Diabetes. 45. 1037-1043 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kimura,T.: "Accumulation of advanced glycation end products of the Maillard reaction with age in human hippocampal neurons" Neurosci.Lett. 208. 53-56 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Ikeda,K.: "N^ε-(carboxymethyl) lysine protein adduct is a major immunological epitope in proteins modified with advanced glycation end products of the Maillard reaction" Biochemistry. 35. 8075-8083 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hiriuchi,S.: "AGE-modified proteins and their potential relevance to atherosclerosis." Trends in Cardiovascular Medicine. 6. 163-168 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hammes,H-P.: "Modification of vitronectin by advanced glycation alters functional properties in vitro and in the diabetic retina" Lab.Invest.75. 325-338 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kimura,T.: "Identification of advanced glycation end products of the Maillard reaction in Pick's disease" Neurosci.Lett. 219. 95-98 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hamada,Y.: "Rapid formation of advanced glycation end products by intermediate metabolites of glycolytic pathway and polyol pathway." Biochem.Biophys.Res.Commun.228. 539-543 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Higashi,T.: "The receptor for advanced glycation end products mediates the chemotaxis of rabbit smooth muscle cells" Diabetes. 46. 463-472 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Smestrod,B.: "Advanced glycation end products are eliminated by scavenger-receptor mediated endocytosis in hepatic sinusoidal Kupffer and endothelial cells" Biochem.J.322. 567-573 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Suzuki,H.: "A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection" Nature. 386. 292-296 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Mizutari,K.: "Photo-enhanced modification of human skin elastin in actinic elastosis by N^ε-(carboxymethyl) lysine,one of the glycoxidation products of the Maillard reaction" J.Invest.Dermatol.(in press). (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Araki, N.: "Macrophage scavenger receptor mediates the endocytic uptake of advanced glycation endproducts of the Maillard reaction" Eur.J.Biochem. 230. 408-415 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kume, S.: "Immunohistrochemical and ultrastructural detection of advanced glycation end products in atherosclerotic lesions of human aorta using a novel specific monoclonal antibody" Am.J.Pathol. 147. 654-667 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Makino, H.: "Ultrastructure of nonenzymatically glycated mesangial matrix in diabetic nephropathy" Kidney International. 48. 517-526 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Saishoji, T.: "Advanced glycation end products stimulate plasminogen activator activity via GM-CSF in RAW264.7 cells" Biochem.Biophys.Res.Commun.217. 278-285 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Miyata, T.: "Identification of pentosidine as a native structure for advanced glycation end products in b2-microglobulin forming amyloid fibrils in patients with dialysis-related amyloidosis" Proc, Natl.Acad.Sci.USA. 93. 2353-2358 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Meng, J.: "Advanced glycation end-products of the Maillard reaction in aortic pepsin-insoluble collagen from diabetic rats" Diabetes. 45. 1037-1043 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kimura, T.: "Accumulation of advanced glycation end products of the Maillard reaction with age in human hippocampal neurons" Neurosci.Lett. 208. 53-56 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Ikeda, K.: "N^<epsilon>- (carboxymethyl) lysine protein adduct is a major immunological epitope in proteins modified with advanced glycation end products of the Maillard reaction" Biochemistry. 35. 8075-8083 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Horiuchi, S.: "AGE-modified proteins and their potential relevance to atherosclerosis" Trends in Cardiovascular Medicine. 6. 163-168 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hammes, H-P.: "Modification of vitronectin by advanced glycation alters functional properties in vitro and in the diabetic retina" Lab.Invest. 75. 325-338 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kimura, T.: "Identification of advanced glycation end products of the Maillard reaction in Pick's disease" Neurosci.Lett. 219. 95-98 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hamada, Y.: "Rapid formation of advanced glycation end products by intermediate metabolites of glycolytic pathway and polyol pathway" Biochem.Biophys.Res.Commun. 228. 539-543 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Higashi, T.: "The receptor for advanced glycation end products mediates the chemotaxis of rabbit smooth muscle cells" Diabetes. 46. 463-472 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Smestrod, B.: "Advanced glycation end products are eliminated by scavenger-receptor mediated endocytosis in hepatic sinusoidal Kupffer and endothelial cells" Biochem J.322. 567-573 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Suzuki, H.: "A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection" Nature. 386. 292-296 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Mizutari, K.: "Photo-enhanced modification of human skin elastin in actinic elastosis by N^<epsilon>- (carboxymethyl) lysine, one of the glycoxidation products of the Maillard reaction" J.Invest.Dermatol. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Miyata,T.et al.: "Identification of pentosidine as a native structure for advanced glycation end products in β2-microglobulin forming amyloid fibrils in patients with dialysis-related amyloidosis" Proc,Natl.Acad.Sci.USA.93. 2353-2358 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Meng,J.et al.: "Advanced glycation end-products of the Maillard reaction in aortic pepsin-insoluble collagen from diabetic rats" Diabetes,. 45. 1037-1043 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Horiuchi,S.: "AGE-modified proteins and their potential relevance to atherosclerosis" Trends in Cardiovascular Medicine. 6.163-168. (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hammes,H-P.et al.: "Modification of vitronectin by advanced glycation alters functional properties in vitro and in the diabetic retina" Lab.Invest.75. 325-338 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Higashi,T.et al.: "The receptor for advanced glycation end products Mediates the chemotaxis of rabbit smooth muscle cells" Diabetes. 46. 463-472 (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Suzuki,H.et al.: "Resistance to atherosclerosis and susceptibility to infection in scavenger receptor knokout mice" Narure. (In press). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Norie Araki: "Macrophage scavenger receptor inediates the endocytic uptake of advanced glycation end-products of the Maillard reaction." Eur.J.Biochem.230. 408-415 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Shuichi Kume: "Immunohistrochemical and ultrastrucutral detection of advanced glycation end products in atherosclerotic lesions of human aorta using a novel specific monoclonal antibody." Am.J.Pathol.147. 654-667 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Hirofumi Makino: "Ultrastructure of nonenzymatically glycated mesangial matrix in diabetic nephrophathy." Kidney International. 48. 517-526 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Tetsushi Saishoji: "Advanced glycation end products stimulate plasminogen activator activity via GM-CSF in RAW264.7 cells." Biochem.Biophys.Res.Commun.217. 278-285 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Toshiro Miyata: "Identification of pentosidine as a native structure for advanced glycation end products in β2-microglobulin forming amyloid fibrils in patients with dialysis-related amyloidosis." Proc,Natl.Acad.Sci.USA.(in press). (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Seikoh Horiuchi: "Advanced glycation end products (AGE) and their recognition by macrophage and macrophage-derived cells." Diabetes. (in press). (1996)

    • Related Report
      1995 Annual Research Report

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Published: 1995-04-01   Modified: 2016-04-21  

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