title: Dimerumic acid attenuates receptor for advanced glycation endproducts signal to inhibit inflammation and diabetes mediated by Nrf2 activation and promotes methylglyoxal metabolism into d-lactic acid.
abstract: This study was designed to evaluate the effects of dimerumic acid (DMA) on receptor for advanced glycation endproducts (RAGE) signal activation and THP-1 monocyte inflammation treated with S100b, a specific ligand of RAGE. We found that DMA inhibited inflammatory cytokine production via upregulation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and alleviated oxidative stress through attenuation of p47phox translocation to the membrane of S100b-treated THP-1 monocytes. We found that DMA activated Nrf2 mediated by the p38 kinase pathway in THP-1 monocytes. However, anti-inflammatory activity of DMA was attenuated by Nrf2 siRNA treatment. In an animal model, methylglyoxal (MG; 200mg/kg bw) was chosen to induce diabetes in Balb/C mice (6 weeks) in this work. The in vivo verification of anti-inflammation in peripheral blood mononuclear cells by DMA treatment was confirmed by tumor necrosis factor-α and interleukin-1β measurements. Oral glucose tolerance test, insulin tolerance test, hyperinsulinemia, and hyperglycemia were improved in MG-treated mice by DMA treatment and these effects were greater than those of silymarin and N-acetylcysteine. Furthermore, DMA increased hepatic glyoxalase mRNA and glutathione mediated by Nrf2 activation to metabolize MG into d-lactic acid, thereby reducing serum and hepatic AGE levels and suppressing inflammatory factor generation in MG-treated mice. However, DMA did not exert the antiglycation activity in MG-bovine serum albumin incubation. Taken together, the results indicate that DMA is a novel antioxidant and Nrf2 activator that lowers AGE levels and may prove to be an effective treatment for diabetes.
authors: Department of Biochemical Science & Technology, College of Life Science, National Taiwan University, Taipei 10617, Taiwan.
authors: Bao-Hong
authors: BH
authors: Lee
authors: Wei-Hsuan
authors: WH
authors: Hsu
authors: Ya-Wen
authors: YW
authors: Hsu
authors: Tzu-Ming
authors: TM
authors: Pan
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054659:Diketopiperazines / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011765:Pyruvaldehyde / Q000378:metabolism / Q000494:pharmacology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000975:Antioxidants; D054659:Diketopiperazines; D017127:Glycation End Products, Advanced; D006877:Hydroxamic Acids; D007328:Insulin; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha; C552122:dimerumic acid; D019344:Lactic Acid; D011765:Pyruvaldehyde; D005947:Glucose