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

Chun Chen; Ze-Feng Zhu; Wen-Xing Nie; Yong Zou

doi:10.1055/a-1528-1760

Planta Medica, Table of Contents

Planta Med 2022; 88(08): 628-638
DOI: 10.1055/a-1528-1760

Biological and Pharmacological Activity

Original Papers

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

Chun Chen

¹School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China

,

Ze-Feng Zhu

¹School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China

²Department of Pharmacy, the Fifth Affiliated Hospital of Jinan University, Heyuan, Guangdong, China

,

Wen-Xing Nie

¹School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China

,

Yong Zou

¹School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China

³Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, Guangzhou, Guangdong, China

› Author Affiliations

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

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References

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

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