Abstract
A prenylated flavonoid, cudraflavanone B, is isolated from Cudrania tricuspidata. In this study, we investigated its anti-inflammatory and anti-neuroinflammatory effects in lipopolysaccharide (LPS)-induced RAW264.7 and BV2 cells. In our initial study of the anti-inflammatory effects of cudraflavanone B the production of nitric oxide and prostaglandin E2 was attenuated in LPS-stimulated RAW264.7 and BV2 cells. These inhibitory effects were related to the downregulation of inducible nitric oxide synthase and cyclooxygenase-2. In addition, cudraflavanone B suppressed the production of pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-α in LPS-induced RAW264.7 and BV2 cells. Moreover, the evaluation of the molecular mechanisms underlying the anti-inflammatory effects of cudraflavanone B revealed that the compound attenuated the nuclear factor-kappa B signaling pathway in LPS-induced RAW264.7 and BV2 cells. In addition, cudraflavanone B inhibited the phosphorylation of extracellular signal-regulated kinase mitogen-activated protein kinase signaling pathways in these LPS-stimulated cells. Thus, cudraflavanone B suppressed nuclear factor-κB, and extracellular signal-regulated kinase mitogen-activated protein kinase mediated inflammatory pathways, demonstrating its potential in the treatment of neuroinflammatory conditions.
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The data and material used and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Liang, D., F. Li, Y. Fu, Y. Cao, X. Song, T. Wang, W. Wang, M. Guo, E. Zhou, D. Li, Z. Yang, and N. Zhang. 2014. Thymol inhibits LPS-stimulated inflammatory response via down-regulation of NF-κB and MAPK signaling pathways in mouse mammary epithelial cells. Inflammation 37 (1): 214–222.
Choi, Y.H., G.Y. Jin, G.Z. Li, and G.H. Yan. 2011. Cornuside suppresses lipopolysaccharide-induced inflammatory mediators by inhibiting nuclear factor-kappa B activation in RAW 264.7 macrophages. Biological & Pharmaceutical Bulletin 34 (7): 959–966.
Wang, X., S.A. Tang, R. Wang, Y. Qiu, M. Jin, and D. Kong. 2015. Inhibitory effects of JEUD-38, a new sesquiterpene lactone from Inula japonica Thunb, on LPS-induced iNOS expression in RAW264.7 cells. Inflammation 38 (3): 941–948.
Ahn, C.B., W.K. Jung, S.J. Park, Y.T. Kim, W.S. Kim, and J.Y. Je. 2016. Gallic acid-g-chitosan modulates inflammatory responses in LPS-stimulated RAW264.7 cells via NF-κB, AP-1, and MAPK pathways. Inflammation 39 (1): 366–374.
Ryu, Y.B., M.J. Curtis-Long, J.W. Lee, H.W. Ryu, J.Y. Kim, W.S. Lee, and K.H. Park. 2009. Structural characteristics of flavanones and flavones from Cudrania tricuspidata for neuraminidase inhibition. Bioorganic & Medicinal Chemistry Letters 19 (17): 4912–4915.
Cho, S.S., J.H. Yang, K.H. Seo, S.M. Shin, E.Y. Park, S.S. Cho, G.U. Jo, J.H. Eo, J.S. Park, D.S. Oh, J.B. Kim, C.S. Na, S.K. Ku, I.J. Cho, and S.H. Ki. 2019. Cudrania tricuspidata extract and its major constituents inhibit oxidative stress-induced liver injury. Journal of Medicinal Food 22 (6): 602–613.
You, Y., S. Min, Y.H. Lee, K. Hwang, and W. Jun. 2017. Hepatoprotective effect of 10% ethanolic extract from Curdrania tricuspidata leaves against ethanol-induced oxidative stress through suppression of CYP2E1. Food and Chemical Toxicology 108 (Pt A): 298–304.
Lee, E.G., H.J. Yun, S.I. Lee, and W.H. Yoo. 2010. Ethyl acetate fraction from Cudrania tricuspidata inhibits IL-1beta-stimulated osteoclast differentiation through downregulation of MAPKs, c-Fos and NFATc1. The Korean Journal of Internal Medicine 25 (1): 93–100.
Kwon, S.B., M.J. Kim, J.M. Yang, H.P. Lee, J.T. Hong, H.S. Jeong, E.S. Kim, and D.Y. Yoon. 2016. Cudrania tricuspidata stem extract induces apoptosis via the extrinsic pathway in SiHa cervical cancer cells. PLoS One 11 (3): e0150235.
Nam, S., H.W. Jang, and T. Shibamoto. 2012. Antioxidant activities of extracts from teas prepared from medicinal plants, Morus alba L., Camellia sinensis L., and Cudrania tricuspidata, and their volatile components. Journal of Agricultural and Food Chemistry 60 (36): 9097–9105.
Kim, D.H., S. Lee, Y.W. Chung, B.M. Kim, H. Kim, K. Kim, and K.M. Yang. 2016. Antiobesity and antidiabetes effects of a Cudrania tricuspidata hydrophilic extract presenting PTP1B inhibitory potential. BioMed Research International 2016: 8432759.
Chang, S.H., E.J. Jung, D.G. Lim, B. Oyungerel, K.I. Lim, E. Her, W.S. Choi, M.H. Jun, K.D. Choi, D.J. Han, and S.C. Kim. 2008. Anti-inflammatory action of Cudrania tricuspidata on spleen cell and T lymphocyte proliferation. The Journal of Pharmacy and Pharmacology 60 (9): 1221–1226.
Kwon, J., N.T. Hiep, D.W. Kim, S. Hong, Y. Guo, B.Y. Hwang, H.J. Lee, W. Mar, and D. Lee. 2016. Chemical constituents isolated from the root bark of Cudrania tricuspidata and their potential neuroprotective effects. Journal of Natural Products 79 (8): 1938–1951.
Shim, J.U., and K.T. Lim. 2009. Inhibitory effect of glycoprotein isolated from Cudrania tricuspidata bureau on expression of inflammation-related cytokine in bisphenol A-treated HMC-1 cells. Inflammation 32 (4): 211–217.
Yoon, C.S., D.C. Kim, T.H. Quang, J. Seo, D.G. Kang, H.S. Lee, H. Oh, and Y.C. Kim YC. 2016. A prenylated xanthone, Cudratricusxanthone A, isolated from Cudrania tricuspidata inhibits lipopolysaccharide-induced neuroinflammation through inhibition of NF-κB and p38 MAPK pathways in BV2 microglia. Molecules 21 (9): E1240.
Rho, Y.H., B.W. Lee, K.H. Park, and Y.S. Bae. 2007. Cudraflavanone A purified from Cudrania tricuspidata induces apoptotic cell death of human leukemia U937 cells, at least in part, through the inhibition of DNA topoisomerase I and protein kinase C activity. Anti-Cancer Drugs 18 (9): 1023–1028.
Kim, K.W., T.H. Quang, W. Ko, D.C. Kim, C.S. Yoon, H. Oh, and Y.C. Kim. 2018. Anti-neuroinflammatory effects of cudraflavanone A isolated from the chloroform fraction of Cudrania tricuspidata root bark. Pharmaceutical Biology 56 (1): 192–200.
Oh, P.S., and K.T. Lim. 2011. Anti-inflammatory effect of glycoprotein isolated from Cudrania tricuspidata Bureau: Involvement of MAPK/NF-κB signaling. Immunological Investigations 40 (1): 76–91.
Fukai, T., M. Yonekawa, A.J. Hou, T. Nomura, H.D. Sun, and J. Uno. 2003. Antifungal agents from the roots of Cudrania cochinchinensis against Candida, Cryptococcus, and Aspergillus species. Journal of Natural Products 66 (8): 1118–1120.
Quang, T.H., N.T. Ngan, C.S. Yoon, K.H. Cho, D.G. Kang, H.S. Lee, Y.C. Kim, and H. Oh. 2015. Protein tyrosine phosphatase 1B inhibitors from the roots of Cudrania tricuspidata. Molecules 20 (6): 11173–11183.
Ko, W., J.H. Sohn, J.H. Jang, J.S. Ahn, D.G. Kang, H.S. Lee, J.S. Kim, Y.C. Kim, and H. Oh. 2016. Inhibitory effects of alternaramide on inflammatory mediator expression through TLR4-MyD88-mediated inhibition of NF-κB and MAPK pathway signaling in lipopolysaccharide-stimulated RAW264.7 and BV2 cells. Chemico-Biological Interactions 244: 16–26.
Titheradge, M.A. 1998. The enzymatic measurement of nitrate and nitrite. Methods in Molecular Biology 100: 83–91.
Kim, D.C., C.S. Yoon, T.H. Quang, W. Ko, J.S. Kim, H. Oh, and Y.C. Kim. 2016. Prenylated flavonoids from Cudrania tricuspidata suppress lipopolysaccharide-induced neuroinflammatory activities in BV2 microglial cells. International Journal of Molecular Sciences 17 (2): 255.
Li, X.J., K.W. Kim, D.C. Kim, H. Oh, X.Q. Liu and Y.C. Kim. 2019. Three novel monoterpenoid glycosides from fruits of Eleutherococcus henryi. Nat Prod Res. https://doi.org/10.1080/14786419.2019.1645661
Xu, Y., S. Chen, Y. Cao, P. Zhou, Z. Chen, and K. Cheng. 2018. Discovery of novel small molecule TLR4 inhibitors as potent anti-inflammatory agents. European Journal of Medicinal Chemistry 154: 253–266.
Li, R.J., C.Y. Gao, C. Guo, M.M. Zhou, J. Luo, and L.Y. Kong. 2017. The anti-inflammatory activities of two major withanolides from Physalis minima via acting on NF-κB, STAT3, and HO-1 in LPS-stimulated RAW264.7 cells. Inflammation 40 (2): 401–413.
Abarikwu, S.O. 2014. Kolaviron, a natural flavonoid from the seeds of Garcinia kola, reduces LPS-induced inflammation in macrophages by combined inhibition of IL-6 secretion, and inflammatory transcription factors, ERK1/2, NF-κB, p38, Akt, p-c-JUN and JNK. Biochimica et Biophysica Acta 1840 (7): 2373–2381.
Inoue, K. 2006. The function of microglia through purinergic receptors: Neuropathic pain and cytokine release. Pharmacology & Therapeutics 109 (1–2): 210–226.
Carey, A.N., D.R. Fisher, D.F. Bielinski, D.S. Cahoon, and B. Shukitt-Hale. 2020. Walnut-associated fatty acids inhibit LPS-induced activation of BV-2 microglia. Inflammation 43 (1): 241–250.
Navarro, V., E. Sanchez-Mejias, S. Jimenez, C. Muñoz-Castro, R. Sanchez-Varo, J.C. Davila, M. Vizuete, A. Gutierrez, and J. Vitorica. 2018. Microglia in Alzheimer's disease: Activated, dysfunctional or degenerative. Frontiers in Aging Neuroscience 10: 140.
Joe, E.H., D.J. Choi, J. An, J.H. Eun, I. Jou, and S. Park. 2018. Astrocytes, microglia, and Parkinson's disease. Experimental Neurobiology 27 (2): 77–87.
Akira, S., and H. Hemmi. 2003. Recognition of pathogen-associated molecular patterns by TLR family. Immunology Letters 85 (2): 85–95.
Cao, X., Y. Jin, H. Zhang, L. Yu, X. Bao, F. Li, and Y. Xu. The anti-inflammatory effects of 4-((5-bromo-3-chloro-2-hydroxybenzyl) amino)-2-hydroxybenzoic acid in lipopolysaccharide-activated primary microglial cells. Inflammation 41(2): 530–540.
Blantz, R.C., and K. Munger. 2002. Role of nitric oxide in inflammatory conditions. Nephron 90 (4): 373–378.
Förstermann, U., and W.C. Sessa. 2012. Nitric oxide synthases: Regulation and function. European Heart Journal 33 (7): 829-837–837a-837d.
Whittle, B.J. 1995. Nitric oxide in physiology and pathology. The Histochemical Journal 27 (10): 727–737.
Ivanov, A.I., and A.A. Romanovsky. 2004. Prostaglandin E2 as a mediator of fever: Synthesis and catabolism. Frontiers in Bioscience 9: 1977–1993.
Andreasson, K. 2010. Emerging roles of PGE2 receptors in models of neurological disease. Prostaglandins & Other Lipid Mediators 91 (3–4): 104–112.
Sales, K.J., and H.N. Jabbour. 2003. Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium. Reproduction 126 (5): 559–567.
Jacques, A., C. Bleau, C. Turbide, N. Beauchemin, and L. Lamontagne. 2009. Macrophage interleukin-6 and tumour necrosis factor-alpha are induced by coronavirus fixation to toll-like receptor 2/heparan sulphate receptors but not carcinoembryonic cell adhesion antigen 1a. Immunology 128 (1 Suppl): e181–e192.
Gabay, C. 2006. Interleukin-6 and chronic inflammation. Arthritis Research & Therapy 8 (Suppl 2): S3.
Scheller, J., A. Chalaris, D. Schmidt-Arras, and S. Rose-John. 2011. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochimica et Biophysica Acta 1813 (5): 878–888.
Zelová, H., and J. Hošek. 2013. TNF-α signalling and inflammation: Interactions between old acquaintances. Inflammation Research 62 (7): 641–651.
Popa, C., M.G. Netea, P.L. van Riel, J.W. van der Meer, and A.F. Stalenhoef. 2007. The role of TNF-alpha in chronic inflammatory conditions, intermediary metabolism, and cardiovascular risk. Journal of Lipid Research 48 (4): 751–762.
Liu, T., L. Zhang, D. Joo, and S.C. Sun. 2017. NF-κB signaling in inflammation. Signal Transduction and Targeted Therapy 2: 17023.
Wu, X., H. Gao, W. Sun, J. Yu, H. Hu, Q. Xu, and X. Chen. 2017. Nepetoidin B, a natural product, inhibits LPS-stimulated nitric oxide production via modulation of iNOS mediated by NF-κB/MKP-5 pathways. Phytotherapy Research 31 (7): 1072–1077.
Pahl, H.L. 1999. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 18 (49): 6853–6866.
Coskun, M., J. Olsen, J.B. Seidelin, and O.H. Nielsen. 2011. MAP kinases in inflammatory bowel disease. Clinica Chimica Acta 412 (7–8): 513–520.
Thalhamer, T., M.A. McGrath, and M.M. Harnett. 2008. MAPKs and their relevance to arthritis and inflammation. Rheumatology (Oxford) 47 (4): 409–414.
Qin, S., C. Yang, W. Huang, S. Du, H. Mai, J. Xiao, and T. Lü. 2018. Sulforaphane attenuates microglia-mediated neuronal necroptosis through down-regulation of MAPK/NF-κB signaling pathways in LPS-activated BV-2 microglia. Pharmacological Research 133: 218–235.
Lim, H.S., Y.J. Kim, B.Y. Kim, and S.J. Jeong. 2019. Bakuchiol suppresses inflammatory responses via the downregulation of the p38 MAPK/ERK signaling pathway. International Journal of Molecular Sciences 20 (14): E3574.
Ngabire, D., Y.A. Seong, M.P. Patil, I. Niyonizigiye, Y.B. Seo, and G.D. Kim. 2018. Anti-inflammatory effects of Aster incisus through the inhibition of NF-κB, MAPK, and Akt pathways in LPS-stimulated RAW 264.7 macrophages. Mediators of Inflammation 2018: 4675204.
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The current study was supported by a research fund from Chosun University in 2016 (K207334002).
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Ko, W., Kim, KW., Quang, T.H. et al. Cudraflavanone B Isolated from the Root Bark of Cudrania tricuspidata Alleviates Lipopolysaccharide-Induced Inflammatory Responses by Downregulating NF-κB and ERK MAPK Signaling Pathways in RAW264.7 Macrophages and BV2 Microglia. Inflammation 44, 104–115 (2021). https://doi.org/10.1007/s10753-020-01312-y
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DOI: https://doi.org/10.1007/s10753-020-01312-y