Ascorbic acid reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and improves survival rate in septic mice by activation of Nrf2/HO-1 signals |
| |
| Institution: | 1. Department of Pharmacology, School of Medicine and The Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, Republic of Korea;2. Department of Pharmacology, Dong-A University College of Medicine, Busan 602-714, Republic of Korea;3. School of Biological Sciences, University of Ulsan (HTC), Ulsan 680-749, Republic of Korea;1. Department of Genetic Engineering, Sungkyunkwan University, Suwon, 440-746, Republic of Korea;2. Department of Food Science & Biotechnology, Sungkyunkwan University, Suwon, 440-746, Republic of Korea;3. Department of Oriental Medical Science, Graduate School of East-West Medicine, Kyunghee University, Secheondong, Yongin 446-701, Republic of Korea;4. Natural Products Research Department, Gyeonggi Institute of Science & Technology Promotion, Suwon, 443-270, Republic of Korea;1. Center for Bioenergy, School of Chemical & Biotechnology, SASTRA Deemed University, Thanjavur, 613401, India;2. Department of Chemical Engineering, School of Chemical & Biotechnology, SASTRA Deemed University, Thanjavur, 613401, India;1. Institute of Developmental Biology, School of Life Science, Shandong University, Jinan 250100, PR China;2. Institute of Organic Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, PR China;3. School of Municipal and Environmental Engineering, Shandong Jianzhu University, Jinan 250101, PR China |
| |
| Abstract: | High mobility group box 1 (HMGB1) is now recognized as a late mediator of sepsis. We tested hypothesis that ascorbic acid (AscA) induces heme oxygenase (HO)-1 which inhibits HMGB1 release in lipopolysaccharide (LPS)-stimulated cells and increases survival of septic mice. AscA increased HO-1 protein expression in a concentration- and time-dependent manner via Nrf2 activation in RAW 264.7 cells. HO-1 induction by AscA was significantly reduced by Nrf2 siRNA-transfected cells. Mutation of cysteine to serine of keap-1 proteins (C151S, C273S, and C288S) lost the ability of HO-1 induction by AscA, due to failure of translocation of Nrf-2 to nucleus. The PI3 kinase inhibitor, LY294002, inhibited HO-1 induction by AscA. Oxyhemoglobin (HbO2), LY294002, and ZnPPIX (HO-1 enzyme inhibitor) reversed effect of AscA on HMGB1 release. Most importantly, administration of AscA (200 mg/kg, i.p.) significantly increased survival in LPS-induced endotoxemic mice. In cecal ligation and puncture (CLP)-induced septic mice, AscA reduced hepatic injury and serum HMGB1 and plasminogen activator inhibitor (PAI)-1 in a ZnPPIX-sensitive manner. In addition, AscA failed to increase survival in Nrf2 knockout mice by LPS. Thus, we concluded that high dose of AscA may be useful in the treatment of sepsis, at least, by activation of Nrf2/HO-1 signals. |
| |
| Keywords: | Sepsis Heme oxygenase HMGB1 Phosphatidylinositol-3-kinase Nrf-2 Ascorbic acid Alanine aminotransferase Antioxidant response element Aspartate Aminotransferase Cecal ligation and puncture Carbon monoxide Enzyme-linked immunosorbent assay High-mobility Group Box 1 Heme oxygenase-1 interleukin-1β Kelch-like ECH-associated protein 1 Lipopolysaccharide Nuclear factor- kB NF-E2-related factor Plasminogen activated inhibitor-1 Phosphoinositide 3-kinase Small interfering RNA Tumor necrosis factor Zinc protoporphyrin IX |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
