Suffrutines A and B Inhibit the Expression of Inflammatory Mediators in LPS-Induced RAW264.7 Cells by Suppressing the NF-κB Signaling Pathway

Abstract

Flueggea suffruticosa is a traditional Chinese medicine that has been commonly used for the treatment of inflammatory ailments, including rheumatism and lumbago. Suffrutines A and suffrutines B are a pair of novel E,E and Z,E isomeric indolizidine alkaloids isolated from the roots of F. suffruticosa. However, their anti-inflammatory activity has not been reported thus far. The aim of this study was to investigate the inhibitory effect of inflammatory mediators and possible mechanisms of suffrutines A and B in lipopolysaccharide-induced RAW264.7 cells. Results showed that suffrutines A and B could remarkably inhibit the production of nitric oxide, prostaglandin E₂, interleukin-6, inducible nitric oxide synthase, and cyclooxygenase-2 in lipopolysaccharide-induced RAW264.7 cells. Further evaluation demonstrated that compared with suffrutines A, suffrutines B could more significantly inhibit the phosphorylation of IKKα/β, the degradation of IκBα, and the nuclear translocation of the p65 and p52 subunits in the canonical and non-canonical nuclear factor-κB pathways. Therefore, suffrutines B exhibited more potent inhibitory activity on inflammatory mediators than suffrutines A.

Key words

Euphorbiaceae - Flueggea suffruticosa - inflammatory mediators - NF-κB signaling pathway - RAW264.7 - suffrutines A - suffrutines B

• References

• 1 Medzhitov R. Inflammation 2010: New adventures of an old flame. Cell 2010; 140: 771-776
• 2 Henson PM. Dampening inflammation. Nat Immunol 2005; 6: 1179-1181
• 3 Medzhitov R. Origin and physiological roles of inflammation. Nature 2008; 454: 428-435
• 4 Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract 2014; 105: 141-150
• 5 Tsoupras A, Lordan R, Zabetakis I. Inflammation, not cholesterol, is a cause of chronic disease. Nutrients 2018; 10: 604
• 6 Eisenlohr LC, Rothstein JL. Oncogenic inflammation and autoimmune disease. Autoimmun Rev 2006; 6: 107-114
• 7 Li QT, Verma IM. NF-κB regulation in the immune system. Nat Rev Immunol 2002; 2: 725-734
• 8 Oeckinghaus A, Ghosh S. The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol 2009; 1: a000034
• 9 Gilmore TD. Introduction to NF-kappaB: Players, pathways, perspectives. Oncogene 2006; 25: 6680-6684
• 10 Hayden MS, Ghosh S. Shared principles in NF-kappaB signaling. Cell 2008; 132: 344-362
• 11 Mitchell JP, Carmody RJ. NF-κB and the transcriptional control of inflammation. Int Rev Cell Mol Biol 2018; 335: 41-84
• 12 Sun SC. The non-canonical NF-κB pathway in immunity and inflammation. Nat Rev Immunol 2017; 17: 545-558
• 13 Razani B, Reichardt AD, Cheng GH. Non-canonical NF-κB signaling activation and regulation: Principles and perspectives. Immunol Rev 2011; 244: 44-54
• 14 Shi G, Li D, Fu JL, Sun Y, Li YR, Qu RF, Jin X, Li DF. Upregulation of cyclooxygenase-2 is associated with activation of the alternative nuclear factor kappa B signaling pathway in colonic adenocarcinoma. Am J Transl Res 2015; 7: 1612-1620
• 15 Park MH, Hong JT. Roles of NF-κB in cancer and inflammatory diseases and their therapeutic approaches. Cells 2016; 5: 15
• 16 Baker RG, Hayden MS, Ghosh S. NF-κB, inflammation, and metabolic disease. Cell Metab 2011; 13: 11-22
• 17 Zhou L, Zhao BX, Jiang RW, Huang XJ, Wu ZL, Wang Y, Ye WC. Securinega alkaloids from the fruits of Flueggea suffruticosa . J Asian Nat Prod Res 2014; 16: 593-601
• 18 Yuan W, Lu ZM, Liu Y, Meng C, Cheng KD, Zhu P. Three new podocarpane-type diterpenoids from callus of Securinega suffruticosa . Chem Pharm Bull 2005; 53: 1610-1612
• 19 Editorial Committee of Nanjing Pharmaceutical College. Chinese herbal Medicine. Nanjing: Jiangsu Peopleʼs Press; 1976: 599-601
• 20 Wu ZL, Zhao BX, Huang XJ, Tang GY, Shi L, Jiang RW, Liu X, Wang Y, Ye WC. Suffrutines A and B: a pair of Z/E isomeric indolizidine alkaloids from the roots of Flueggea suffruticosa . Angew Chem Int Ed Engl 2014; 126: 5906-5909
• 21 Chirkin E, Atkatlian W, Porée FH. The Securinega Alkaloids. Alkaloids Chem Biol 2015; 74: 1-120
• 22 Zhu ZF, Chen C, Jiang JX, Zhang QZ, Du ZB, Wei SX, Song XH, Tang J, Lei JP, Ke ZF, Zou Y. Synthesis and biological evaluation of suffrutines A, B and their N-fused analogues. Org Chem Front 2020; 7: 1122-1131
• 23 Endale M, Park SC, Kim S, Kim SH, Yang YY, Cho JY, Rhee MH. Quercetin disrupts tyrosine-phosphorylated phosphatidylinositol 3-kinase and myeloid differentiation factor-88 association, and inhibits MAPK/AP-1 and IKK/NF-κB-induced inflammatory mediators production in RAW264.7 cells. Immunobiology 2013; 218: 1452-1467
• 24 Sakthivel KM, Guruvayoorappan C. Acacia ferruginea inhibits inflammation by regulating inflammatory iNOS and COX-2. J Immunotoxicol 2016; 13: 127-135
• 25 Morgan D, Garg M, Tergaonkar V, Tan SY, Sethi G. Pharmacological significance of the non-canonical NF-κB pathway in tumorigenesis. Biochim Biophys Acta Rev Cancer 2020; 1874: 188449
• 26 Deng WG, Tang ST, Tseng HP, Wu KK. Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p 52 acetylation and binding. Blood 2006; 108: 518-524
• 27 Pereira-Leite C, Nunes C, Jamal SK, Cuccovia IM, Reis S. Nonsteroidal anti-inflammatory therapy: A journey toward safety. Med Res Rev 2017; 37: 802-859
• 28 Dhingra AK, Chopra B, Dass R, Mittal SK. An update on anti-inflammatory compounds: A review. Antiinflamm Antiallergy Agents Med Chem 2015; 14: 81-97
• 29 Dar KB, Bhat AH, Amin S, Masood A, Zargar MA, Ganie SA. Inflammation: a multidimensional insight on natural anti-inflammatory therapeutic compounds. Curr Med Chem 2016; 23: 3775-3800
• 30 Wu MY, Lu JH. Autophagy and macrophage functions: Inflammatory response and phagocytosis. Cells 2019; 9: 70
• 31 Matsuno R, Aramaki Y, Arima H, Adachi Y, Ohno N, Yadomae T, Tsuchiya S. Contribution of CR3 to nitric oxide production from macrophages stimulated with high-dose of LPS. Biochem Biophys Res Commun 1998; 244: 115-119
• 32 Nakanishi-Matsui M, Yano S, Matsumoto N, Futai M. Lipopolysaccharide induces multinuclear cell from RAW264.7 line with increased phagocytosis activity. Biochem Biophys Res Commun 2012; 425: 144-149
• 33 Pi J, Li T, Liu JX, Su XH, Wang R, Yang F, Bai HH, Jin H, Cai JY. Detection of lipopolysaccharide induced inflammatory responses in RAW264.7 macrophages using atomic force microscope. Micron 2014; 65: 1-9