Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Dimethyl Cardamonin Exhibits Anti-inflammatory Effects via Interfering with the PI3K-PDK1-PKCα Signaling Pathway

  • Yu, Wan-Guo (State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology) ;
  • He, Hao (State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology) ;
  • Yao, Jing-Yun (State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology) ;
  • Zhu, Yi-Xiang (State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology) ;
  • Lu, Yan-Hua (State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology)
  • Received : 2015.04.29
  • Accepted : 2015.06.18
  • Published : 2015.11.01
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Abstract

Consumption of herbal tea [flower buds of Cleistocalyx operculatus (Roxb.) Merr. et Perry (Myrtaceae)] is associated with health beneficial effects against multiple diseases including diabetes, asthma, and inflammatory bowel disease. Emerging evidences have reported that High mobility group box 1 (HMGB1) is considered as a key "late" proinflammatory factor by its unique secretion pattern in aforementioned diseases. Dimethyl cardamonin (2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone, DMC) is a major ingredient of C. operculatus flower buds. In this study, the anti-inflammatory effects of DMC and its underlying molecular mechanisms were investigated on lipopolysaccharide (LPS)-induced macrophages. DMC notably suppressed the mRNA expressions of TNF-${\alpha}$, IL-$1{\beta}$, IL-6, and HMGB1, and also markedly decreased their productions in a time- and dose-dependent manner. Intriguingly, DMC could notably reduce LPS-stimulated HMGB1 secretion and its nucleo-cytoplasmic translocation. Furthermore, DMC dose-dependently inhibited the activation of phosphatidylinositol 3-kinase (PI3K), phosphoinositide-dependent kinase 1 (PDK1), and protein kinase C alpha (PKC${\alpha}$). All these data demonstrated that DMC had anti-inflammatory effects through reducing both early (TNF-${\alpha}$, IL-$1{\beta}$, and IL-6) and late (HMGB1) cytokines expressions via interfering with the PI3K-PDK1-PKC${\alpha}$ signaling pathway.

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References

  1. Abraham, E., Anzueto, A., Gutierrez, G., Tessler, S., Pedro, G. S., Wunderink, R., Nogare, A. D., Nasraway, S., Berman, S., Cooney, R., Levy, H., Baughrnan, R., Rurnbak, M., Light, R. B., Poole, L., Allred, R., Constant, J., Pennington, J. and Porter, S. (1998) Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. Lancet 351, 929-933. https://doi.org/10.1016/S0140-6736(05)60602-2
  2. Andersson, U., Wang, H. C., Palmblad, K., Aveberger, A.C., Bloom, O., Helena, E. H., Janson, A., Kokkola, R., Zhang, M. A., Yang, H. and Tracey, K. J. (2000) High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J. Exp. Med. 192, 565-570. https://doi.org/10.1084/jem.192.4.565
  3. Amor, E. C., Villasenor, I. M., Ghayur, M. N., Gilani, A. H. and Choudhary, M. I. (2005) Spasmolytic flavonoids from Syzygium samarangense (Blume) Merr. & L.M Perry. Z. Naturforsch. C 60, 67-71.
  4. Bonaldi, T., Talamo, F., Scaffidi, P., Ferrera, D., Porto, A., Bachi, A., Rubartelli, A., Agresti, A. and Bianchi, M. E. (2003) Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 22, 5551-5560. https://doi.org/10.1093/emboj/cdg516
  5. Cheng, C., Huang, C., Ma, T. T., Bian, E. B., He, Y., Zhang, L. and Li, J. (2014) SOCS1 hypermethylation mediated by DNMT1 is associated with lipopolysaccharide- induced inflammatory cytokines in macrophages. Toxicol. Lett. 225, 488-497. https://doi.org/10.1016/j.toxlet.2013.12.023
  6. Charles, F., Jean-Francois, A. D., Steven, O., John, P., Robert, B., Gus, S., Thomas, I., Eric, R. and Marc, S. (1994) Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome, results from a randomized, double-blind, placebo-controlled trial. J. Am. Med. Assoc. 271, 1836-1843. https://doi.org/10.1001/jama.1994.03510470040032
  7. Czura, C. J., Yang, H., Amella, C. A. and Tracey, K. J. (2004) HMGB1 in the immunology of sepsis (Not septic shock) and arthritis. Adv. Immunol. 84, 181-200. https://doi.org/10.1016/S0065-2776(04)84005-7
  8. Dung, N. T., Kim, J. M. and Kang, S. C. (2008) Chemical composition, antimicrobial and antioxidant activities of the essential oil and the ethanol extract of Cleistocalyx operculatus (Roxb.) Merr and Perry buds. Food Chem. Toxicol. 46, 3632-3639. https://doi.org/10.1016/j.fct.2008.09.013
  9. Dao, T. T., Tung, B. T., Nguyen, P. H., Thuong, P. T., Yoo, S. S., Kim, E. H., Kim, S. K. and Oh, W. K. (2010) C-methylated flavonoids from Cleistocalyx operculatus and their inhibitory effects on novel influenza a (H1N1) neuraminidase. J. Nat. Prod. 73, 1636-1642. https://doi.org/10.1021/np1002753
  10. De-Geus, E. D. and Vervelde, L. (2013) Regulation of macrophage and dendritic cell function by pathogens and through immunomodulation in the avian mucosa. Dev. Comp. Immunol. 41, 341-351. https://doi.org/10.1016/j.dci.2013.03.008
  11. Edward, A., Richard, W., Henry, S., Trish, P., Stanley, N., Howard, L., Roger, B., Richard, W., Robert, B. and Randy, A. (1995) Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome, a randomized controlled, double-blind, multicenter clinical trial. J. Am. Med. Assoc. 273, 934-941. https://doi.org/10.1001/jama.1995.03520360048038
  12. Ghayur, M. N., Gilani, A. H., Khan, A., Amor, E. C., Villasenor, I. M. and Choudhary, M. I. (2006) Presence of calcium antagonist activity explains the use of Syzygium samarangense in diarrhoea. Phytother. Res. 20, 49-52. https://doi.org/10.1002/ptr.1801
  13. Gong, G., Xiang, L., Yuan, L. B., Hu, L., Wu, W., Cai, L., Yin, L. and Dong, H. (2014) Protective effect of glycyrrhizin, a direct HMGB1 inhibitor, on focal cerebral ischemia/reperfusion-induced inflammation, oxidative stress, and apoptosis in rats. PLoS One 9, 89450-89460. https://doi.org/10.1371/journal.pone.0089450
  14. Hirahara, K., Poholek, A., Vahedi, G., Laurence, A., Kanno, Y., Milner, J. D. and O'Shea, J. J. (2013) Mechanisms underlying helper Tcell plasticity, implications for immune-mediated disease. J. Allergy Clin. Immunol. 131, 1276-1287. https://doi.org/10.1016/j.jaci.2013.03.015
  15. Hu, Y. C., Luo, Y. D., Li, L., Joshi, M. K. and Lu, Y. H. (2012) In vitro investigation of 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone for glycemic control. J. Agric. Food Chem. 60, 10683-10688. https://doi.org/10.1021/jf303078r
  16. Hu, Y. C., Zhang, Z., Shi, W. G., Mi, T. Y., Zhou, L. X., Huang, N., Hoptroff, M. and Lu, Y. H. (2014a) 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone promoted glucose uptake and imposed a paradoxical effect on adipocyte differentiation in 3T3-L1 cells. J. Agric. Food Chem. 62, 1898-1904. https://doi.org/10.1021/jf405368q
  17. Hu, Y. C., Hao, D. M., Zhou, L. X., Zhang, Z., Huang, N., Hoptroff, M. and Lu, Y. H. (2014b) 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone protects the impaired insulin secretion induced by glucotoxicity in pancreatic ${\beta}$-Cells. J. Agric. Food Chem. 62, 1602-1608. https://doi.org/10.1021/jf405365d
  18. Huang, H. Y., Niu, J. L., Zhao, L. M. and Lu, Y. H. (2011) Reversal effect of 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone on multidrug resistance in resistant human hepatocellular carcinoma cell line BEL-7402/5-FU. Phytomedicine 18, 1086-1092. https://doi.org/10.1016/j.phymed.2011.04.001
  19. Huang, H. Y., Niu, J. L. and Lu, Y. H. (2012) Multidrug resistance reversal effect of DMC derived from buds of Cleistocalyx operculatus in human hepatocellular tumor xenograft model. J. Sci. Food Agric. 92, 135-140. https://doi.org/10.1002/jsfa.4551
  20. Kim, K. N., Heo, S. J., Yoon, W. J., Kang, S. M., Ahn, G., Yi, T. H. and Jeon, Y. J. (2010) Fucoxanthin inhibits the inflammatory response by suppressing the activation of NF-${\kappa}B$ and MAPKs in lipopolysaccharide-induced RAW 264.7 macrophages. Eur. J. Pharmacol. 649, 369-375. https://doi.org/10.1016/j.ejphar.2010.09.032
  21. Lakhan, S. E., Kirchgessner, A. and Hofer, M. (2009) Inflammatory mechanisms in ischemic stroke, therapeutic approaches. J. Transl. Med. 7, 97-108. https://doi.org/10.1186/1479-5876-7-97
  22. Martinez, A., Conde, E., Moure, A., Dominguez, H. and Estevez, R. J. (2012) Protective effect against oxygen reactive species and skin fibroblast stimulation of Couroupita guianensis leaf extracts. Nat. Prod. Res. 26, 314-322. https://doi.org/10.1080/14786411003752094
  23. Mai, T. T., Yamaguchi, K., Yamanaka, M., Lam, N. T., Otsuka, Y. and Chuyen, N. V. (2010) Protective and anticataract effects of the aqueous extract of Cleistocalyx operculatus flower buds on ${\beta}$-Cells of streptozotocin-diabetic rats. J. Agric. Food Chem. 58, 4162-4168. https://doi.org/10.1021/jf904304w
  24. Oozawa, S., Mori, S., Kanke, T., Takahashi, H., Liu, K. Y., Tomono, Y., Asanuma, M., Miyazaki, I., Nishibori, M. and Sano, S. J. (2008) Effects of HMGB1 on ischemia-reperfusion injury in the rat heart. Circ. J. 72, 1178-1184. https://doi.org/10.1253/circj.72.1178
  25. Oh, Y. J., Youn, J. H., Ji, Y., Lee, S. E., Lim, K. J., Choi, J. E. and Shin, J. S. (2009) HMGB1 is phosphorylated by classical protein kinase C and is secreted by a calcium-dependent mechanism. J. Immunol. 182, 5800-5809. https://doi.org/10.4049/jimmunol.0801873
  26. Oh, Y. J., Youn, J. H., Min, H. J., Kim, D. H., Lee, S. S., Choi, I. H. and Shin, J. S. (2011) CKD712, (S)-1-(${\alpha}$-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, inhibits the lipopolysaccharide-stimulated secretion of HMGB1 by inhibiting PI3K and classical protein kinase C. Int. Immunopharmacol. 11, 1160-1165. https://doi.org/10.1016/j.intimp.2011.03.013
  27. Pruitt, J. H., Copel, E. M. and Moldawer, L. L. (1995) Interleukin-1 and interleukin-1 antagonism in sepsis, systemic inflammatory response syndrome, and septic shock. Shock 3, 235-251. https://doi.org/10.1097/00024382-199504000-00001
  28. Su, M. Y., Huang, H. Y., Li, L. and Lu, Y. H. (2011) Protective effects of 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone to PC12 cells against cytotoxicity induced by hydrogen peroxide. J. Agric. Food Chem. 59, 521-527. https://doi.org/10.1021/jf104408d
  29. Salem, M. M. and Werbovetz, K. A. (2005) Antiprotozoal compounds from Psorothamnus polydenius. J. Nat. Prod. 68, 108-111. https://doi.org/10.1021/np049682k
  30. Valledor, A. F., Comalada, M., Santamaria-Babi, L. F., Lloberas, J. and Celada, A. (2010) Macrophage proinflammatory activation and deactivation, aquestion of balance. Adv. Immunol. 108, 1-20. https://doi.org/10.1016/B978-0-12-380995-7.00001-X
  31. Venereau, E., Casalgrandi, M., Schiraldi, M., Antoine, D. J., Cattaneo, A., Marchis, F. D., Liu, J., Antonelli, A., Preti, A., Raeli, L., Shams, S. S., Yang, H., Varani, L., Andersson, U., Tracey, K. J., Bachi, A., Uguccioni, M. and Bianchi, M. E. (2012) Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J. Exp. Med. 209, 1519-1528. https://doi.org/10.1084/jem.20120189
  32. Wang, H. C., Bloom, O., Zhang, M. H., Vishnubhakat, J. M., Ombrellino, M., Che, J. T., Frazier, A., Yang, H., Ivanova, S., Borovikova, L., Manogue, K. R., Faist, E., Abraham, E., Andersson, J., Andersson, U., Molina, P. E., Abumrad, N. N., Sama, A. and Tracey, K. J. (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285, 248-251. https://doi.org/10.1126/science.285.5425.248
  33. Ye, C. L., Lu, Y. H. and Wei, D. Z. (2004) Flavonoids from Cleistocalyx operculatus. Phytochemistry 65, 445-447. https://doi.org/10.1016/j.phytochem.2003.11.002
  34. Ye, C. L., Liu, J. W., Wei, D. Z., Lu, Y. H. and Qian, F. (2005a) In vivo antitumor activity by 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone in a solid human carcinoma xenograft model. Cancer Chemother. Pharmacol. 56, 70-74. https://doi.org/10.1007/s00280-004-0975-y
  35. Ye, C. L., Qian, F., Wei, D. Z., Lu, Y. H. and Liu, J. W. (2005b) Induction of apoptosis in K562 human leukemia cells by 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone. Leuk. Res. 29, 887-892. https://doi.org/10.1016/j.leukres.2005.01.006
  36. Yang, H., Lundback, P., Ottosson, L., Erlandsson-Harris, H., Venereau, E., Bianchi, M. E., Al-Abed, Y., Andersson, L., Tracey, K. J. and Antoine, D. J. (2012) Redox modification of cysteine residues regulates the cytokine activity of High Mobility Group Box-1 (HMGB1). Mol. Med. 18, 250-259.
  37. Yu, W. G., Qian, J. and Lu, Y. H. (2011) Hepatoprotective effects 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone on CCl4-induced acute liver injury in mice. J. Agric. Food Chem. 59, 12821-12829. https://doi.org/10.1021/jf2042032
  38. Youn, J. H. and Shin, J. S. (2006) Nucleocytoplasmic shuttling of HMGB1 is regulated by phosphorylation that redirects it toward secretion. J. Immunol. 177, 7889-7897. https://doi.org/10.4049/jimmunol.177.11.7889
  39. Yang, H., Wang, H. C., Czura, C. J. and Tracey, K. J. (2005) The cytokine activity of HMGB1. J. Leukocyte Biol. 78, 1-8. https://doi.org/10.1189/jlb.1104648
  40. Zhou, H. T., Ji, X. M., Wu, Y., Xuan, J., Qi, Z. L., Shen, L., Lan, L., Li, Q., Yin, Z. M., Li, Z. J. and Zhao, Z. H. (2014) A dual-role of Gu-4 in suppressing HMGB1 secretion and blocking HMGB1 pro-inflammatory activity during inflammation. PLoS One 9, 89634-89645. https://doi.org/10.1371/journal.pone.0089634

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