Impaired gastric ulcer healing in diabetic mice: role of methylglyoxal.
Methylglyoxal is a reactive dicarbonyl compound produced from cellular glycolytic intermediates that reacts non-enzymatically with proteins to form products such as argpyrimidine at arginine residue. The aim of the present study was to investigate the role of methylglyoxal in the delayed healing of gastric ulcer in diabetes, and to identify the methylglyoxal-modified proteins as a target molecule of this modification. Using male C57BL/6 mice, diabetes was induced by a single i.p. injection of streptozotocin and gastric ulcers were produced by the focal application of 40% of acetic acid to the serosal surface of the stomach. In order to evaluate the effect of OPB-9195, an inhibitor of methylglyoxal modification, on gastric ulcer healing, mice were given orally OPB-9195 (30 mg/kg) twice daily for 14 days, one week before and after the injection of streptozotocin. The area of gastric ulcer on day 7 was significantly increased in diabetic mice compared to non-diabetic mice, indicating delayed ulcer healing. This increase in ulcer area in diabetic mice was significantly reversed by the treatment with OPB-9195 without affecting blood glucose levels. Proteomics analysis showed the methylglyoxal-modification of peroxiredoxin 6 proteins in the diabetic gastric mucosa around gastric ulcer, and this modification was markedly inhibited by the treatment with OPB-9195. In conclusion, the present study suggests a link of increased methylglyoxal modification of proteins including peroxiredoxin 6 to the delayed gastric ulcer healing in diabetes, and also shows the therapeutic potential of the inhibitor of methylglyoxal modification for the treatment of diabetic gastric ulcers.
Naito
Y
Y
Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan. ynaito@koto.kpu-m.ac.jp
Takagi
T
T
Oya-Ito
T
T
Okada
H
H
Suzuki
T
T
Hirata
I
I
Hirai
M
M
Uchiyama
K
K
Handa
O
O
Uchida
K
K
Yoshikawa
T
T
D000818:Animals; D000897:Anti-Ulcer Agents / Q000627:therapeutic use; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D005753:Gastric Mucosa / Q000737:chemistry / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D017127:Glycation End Products, Advanced / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D006031:Glycosylation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009952:Ornithine / Q000031:analogs & derivatives / Q000032:analysis; D054465:Peroxiredoxin VI / Q000737:chemistry / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000502:physiology; D011506:Proteins / Q000032:analysis / Q000737:chemistry; D011743:Pyrimidines / Q000032:analysis; D011765:Pyruvaldehyde / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects / Q000502:physiology; D012720:Severity of Illness Index; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology* / Q000517:prevention & control; D013830:Thiadiazoles / Q000627:therapeutic use; D053778:Thiazolidines / Q000627:therapeutic use; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
D000897:Anti-Ulcer Agents; D001786:Blood Glucose; D017127:Glycation End Products, Advanced; C105739:OPB 9195; D011506:Proteins; D011743:Pyrimidines; D013830:Thiadiazoles; D053778:Thiazolidines; C107313:argpyrimidine; D011765:Pyruvaldehyde; D009952:Ornithine; D054465:Peroxiredoxin VI; C515983:Prdx6 protein, mouse