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 |
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| Institution: | 1. Nephrological Research Group, Department of Medicine, Stavanger University Hospital, Stavanger, Norway;2. Department of Transplant Medicine, Oslo University Hospital—Rikshospitalet, Oslo, Norway;3. Department of Natural Sciences, University of Agder, Kristiansand, Norway;1. Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary;2. Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary;3. Experimental and Molecular Immunology and Neurogenetics, The National Center for Scientific Research, Orleans, France;4. Institute of Molecular Medicine, University of Cape Town, Cape Town, South Africa;5. Institute of Nutrition and Food Technology “José Mataix Verdú”, Department of Physiology, Biomedical Research Center, University of Granada, Granada, Spain;1. College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, PR China;2. Department of Microbiology and Plant Pathology, University of California-Riverside, Riverside, CA 92521, USA;3. Faculty of Veterinary and Animal Sciences, The Islamia University of Bahawalpur, 63100, Pakistan;4. Faculty of Veterinary & Animal Sciences, University of Poonch Rawalakot, Azad Jammu & Kashmir, 12350, Pakistan;5. College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea |
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| 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; 200 mg/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. |
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