Anti-inflammatory and Anti-oxidative Activities of Paeonol and Its Metabolites Through Blocking MAPK/ERK/p38 Signaling Pathway
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The possible protective and curative effects of paeonol on carrageenan-induced acute hind paw edema in rats and dextran sulfate sodium (DSS)-induced colitis in mice have been evaluated. After oral administration, paeonol (20 and 40 mg/kg) reduced the edema increase in paw volumes and also the development of DSS-induced murine colitis. Furthermore, anti-inflammatory and anti-oxidant activities of paeonol (1) together with its 10 metabolites (M2~M11) were investigated by using in vitro anti-inflammatory and anti-oxidant assays. M3 and M11 exhibited significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activities (with EC50 values of 93.44 and 23.24 μM, respectively). All the metabolites except M8 showed hydroxyl radical scavenging activities, and M3 and M11 were the most potent agents (with EC50 values of 336.02 and 124.05 μM, respectively). Inhibitory effects of paeonol, M2~M11 on the overproduction of nitric oxide (NO), and the release of TNF-α were also tested. M3 and M11 potently inhibited lipopolysaccharide (LPS)-induced overproduction of NO in macrophage RAW 264.7. Western blot results demonstrated that paeonol, M3, and M11 downregulated the high expression of inducible nitric oxide synthase (iNOS) and COX-2 proteins, and the effects of M3 and M11 were more potent when compared with paeonol. These findings indicated that paeonol may play anti-inflammatory and anti-oxidant roles by changing to its active metabolites after absorption. In addition, further investigations on the mechanism showed that paeonol, M3, and M11 blocked the phosphorylation of MAPK/ERK 1/2 and p38, whereas they showed no effect on the phosphorylation of JNK. The above results suggested that pre-treatment with paeonol might be an effective therapeutic intervention against inflammatory diseases including colitis.
KEY WORDSpaeonol metabolite inflammation oxidative stress MAPK
This work was supported by the State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, and the Taishan Scholar Project to Fenghua Fu, and the Scientific and Technological Project of Yantai City, as well as by the Undergraduate Scientific and Technological Innovation Project of Yantai University.
Conflict of interest
The authors report no conflicts of interest in this work.
- 2.Hong, M.H., J.H. Kim, S.H. Na, H. Bae, Y.C. Shin, S.H. Kim, and S.G. Ko. 2010. Inhibitory effects of Paeonia suffruticosa on allergic reactions by inhibiting the NF-kappaB/I kappaB-alpha signaling pathway and phosphorylation of ERK in an animal model and human mast cells. Bioscience Biotechnology and Biochemistry 74: 1152–1156.CrossRefGoogle Scholar
- 10.Xie, Y., H. Zhou, Y.F. Wong, H.X. Xu, Z.H. Jiang, and L. Liu. 2008. Study on the pharmacokinetics and metabolism of paeonol in rats treated with pure paeonol and an herbal preparation containing paeonol by using HPLC–DAD-MS method. Journal of Pharmaceutical and Biomedical Analysis 46: 748–756.CrossRefPubMedGoogle Scholar
- 13.Ohkawara, T., H. Takeda, K. Kato, K. Miyashita, M. Kato, T. Iwanaga, and M. Asaka. 2005. Polaprezinc (N-(3-aminopropionyl)-L-histidinato zinc) ameliorates dextran sulfate sodium-induced colitis in mice, Scand. Journal of Gastroenterology 40: 1321–1327.Google Scholar
- 23.Jung, H.W., C.H. Yoon, K.M. Park, H.S. Han, and Y.K. Park. 2009. Hexane fraction of zingiberis rhizoma crudus extract inhibits the production of nitric oxide and proinflammatory cytokines in LPS-stimulated BV2 microglial cells via the NF-kappaB pathway. Food and Chemical Toxicology 47: 1190–1197.CrossRefPubMedGoogle Scholar
- 24.Kim, K.N., Y.J. Ko, M.C. Kang, H.M. Yang, S.W. Roh, T. Oda, Y.J. Jeon, W.K. Jung, S.J. Heo, W.J. Yoon, and D. Kim. 2013. Anti-inflammatory effects of trans-1, 3-diphenyl-2, 3-epoxypropane-1-one mediated by suppression of inflammatory mediators in LPS-stimulated RAW 264.7 macrophages. Food and Chemical Toxicology 53: 371–375.CrossRefPubMedGoogle Scholar