Abstract
The anti-inflammatory actions of phytochemicals have attracted much attention due to the current state of numerous inflammatory disorders. Thai traditional medicine uses Maclura cochinchinensis (Lour.) Corner to treat chronic fever and various inflammatory diseases, as well as to maintain normal lymphatic function. Five flavonoids and five xanthones were isolated from the heartwood of M. cochinchinensis and we investigated the anti-inflammatory properties of the isolated compounds. All isolated compounds possessed an anti-inflammatory effect by decreasing prostaglandin E2 (PGE2) synthesis in lipopolysaccharide (LPS)-activated murine macrophages with varying degrees of potency. The greatest decrease in M1 inflammatory mediators, nitric oxide, PGE2, and proinflammatory cytokines was observed with 1,3,7-trihydroxyxanthone and 1,3,5-trihydroxyxanthone treatment of LPS-activated macrophages. The anti-inflammatory mechanism of the two xanthones is mediated by the suppression of inducible nitric oxide synthase, cyclooxygenase-2, and phosphatidylinositol 3-kinase/protein kinase B expression and the upregulation of M2 anti-inflammatory signalling proteins phosphorylated signal transducer and activator of transcription 6 and peroxisome proliferator-activated receptors-γ. 1,3,7-Trihydroxyxanthone exhibits superior induction of anti-inflammatory M2 mediator of LPS-activated macrophages by upregulating arginase1 expression. Following the resolution of inflammation, the two xanthones enhanced surface TLR4 expression compared to LPS-stimulated cells, possibly preserving macrophage function. Our research highlights the role of the two xanthones in modulating the M1/M2 macrophage polarisation to reduce inflammation and retain surface TLR4 once inflammation has been resolved. These findings support the use of xanthones for their anti-inflammatory effects in treating inflammatory dysregulation.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
All data presented in this study are included in the article.
References
Ali M, Arfan M, Ahmad M et al (2011) Anti-inflammatory xanthones from the twigs of Hypericum oblongifolium wall. Planta Med 77:2013–2018. https://doi.org/10.1055/s-0031-1280114
Ali Reza ASM, Nasrin MS, Hossen MA et al (2021) Mechanistic insight into immunomodulatory effects of food-functioned plant secondary metabolites. Crit Rev Food Sci Nutr. https://doi.org/10.1080/10408398.2021.2021138
Ando H, Hirai Y, Fujii M (2007) The chemical constituents of fresh Gentian root. J Nat Med 61:269–279. https://doi.org/10.1007/s11418-007-0143-x
Bunyapraphatsara N, Dechsree S, Yoosook C, Herunsalee A, Panpisutchai Y (2000) Anti-herpes simplex virus component isolated from Maclura cochinchinensis. Phytomedicine 6:421–424
Chen JQ, Szodoray P, Zeher M (2016) Toll-like receptor pathways in autoimmune diseases. Clin Rev Allergy Immunol 50:1–17. https://doi.org/10.1007/s12016-015-8473-z
Chen S, Lu Z, Wang F, Wang Y (2018) Cathelicidin-WA polarizes E. coli K88-induced M1 macrophage to M2-like macrophage in RAW264.7 cells. Int Immunopharmacol 54:52–59. https://doi.org/10.1016/j.intimp.2017.10.013
Chewchinda S, Leakaya N, Sato H, Sato VH (2019) Antidiabetic effects of Maclura cochinchinensis (Lour.) corner heartwood extract. J Tradit Complement Med 11:68–74. https://doi.org/10.1016/j.jtcme.2019.10.004
Chien TV, Anh NT, Thanh NT, Thao TTP, Loc TV, Sung TV (2019) Two new prenylated isoflavones from Maclura cochinchinensis collected in Hoa Binh province Vietnam. Nat Prod Res 33:212–218. https://doi.org/10.1080/14786419.2018.1443096
Chulrik W, Jansakun C, Chaichompoo W et al (2022) Oxocrebanine from Stephania pierrei exerts macrophage anti-inflammatory effects by downregulating the NF-κB, MAPK, and PI3K/Akt signalling pathways. Inflammopharmacol 30:1369–1382. https://doi.org/10.1007/s10787-022-01021-y
Ciesielska A, Matyjek M, Kwiatkowska K (2021) TLR4 and CD14 trafficking and its influence on LPS-induced proinflammatory signaling. Cell Mol Life Sci 78:1233–1261. https://doi.org/10.1007/s00018-020-03656-y
Ciesielska A, Krawczyk M, Sas-Nowosielska H, Hromada-Judycka A, Kwiatkowska K (2022) CD14 recycling modulates LPS-induced inflammatory responses of murine macrophages. Traffic 23:310–330. https://doi.org/10.1111/tra.12842
Department of Thai traditional and alternative medicine, Ministry of Public Health Thailand (2021) National Thai Traditional Medicine Formulary 2021 Edition. Department of Thai Traditional and Alternative Medicine Web.https://fund.dtam.moph.go.th/images/FundDtam2564/1.N-Funddtam01/dl0121-ThaiMed_August2021.pdf. Accessed 4 May 2022
Downey CM, Aghaei M, Schwendener RA, Jirik FR (2014) DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2’3’-cGAMP, induces M2 macrophage repolarization. PLoS ONE 9:e99988. https://doi.org/10.1371/journal.pone.0099988
Endale M, Park SC, Kim S et al (2013) Kim SH, Yang Y, 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 RAW 264.7 cells. Immunobiology 218:1452–1467. https://doi.org/10.1016/j.imbio.2013.04.019
Fitzgerald KA, Kagan JC (2020) Toll-like receptors and the control of immunity. Cell 180:1044–1066. https://doi.org/10.1016/j.cell.2020.02.041
Fouotsa H, Tatsimo SJ, Neumann B (2014) A new xanthone derivative from twigs of Garcinia nobilis. Nat Prod Res 28:1030–1036. https://doi.org/10.1080/14786419.2014.903398
Funes SC, Rios M, Escobar-Vera J, Kalergis AM (2018) Implications of macrophage polarization in autoimmunity. Immunology 154:186–195. https://doi.org/10.1111/imm.12910
Gao S, Wang Y, Li D et al (2019) TanshinoneIIA alleviates inflammatory response and directs macrophage polarization in lipopolysaccharide-stimulated RAW264.7 cells. Inflammation 42:264–275. https://doi.org/10.1007/s10753-018-0891-7
Gardner EM, Sarraf P, Williams EW, Zerega NJC (2017) Phylogeny and biogeography of Maclura (Moraceae) and the origin of an anachronistic fruit. Mol Phylogenet Evol 117:49–59. https://doi.org/10.1016/j.ympev.2017.06.021
Ghosal S, Chaudhuri RK, Nath A (1973) Chemical constituents of gentianaceae. IV. New xanthones of Canscora decussata. J Pharm Sci 62:137–139. https://doi.org/10.1002/jps.2600620128
Gonda R, Takeda T, Akiyama T (2000) Studies on the constituents of Anaxagorea luzonensis A. GRAY Chem Pharm Bull (tokyo) 48:1219–1222. https://doi.org/10.1248/cpb.48.1219
Hawkins PT, Stephens LR (2015) PI3K signalling in inflammation. Biochim Biophys Acta 1851:882–897. https://doi.org/10.1016/j.bbalip.2014.12.006
Hu TY, Ju JM, Mo LH (2019) Anti-inflammation action of xanthones from Swertia chirayita by regulating COX-2/NF-κB/MAPKs/Akt signaling pathways in RAW 264.7 macrophage cells. Phytomedicine 55:214–221. https://doi.org/10.1016/j.phymed.2018.08.001
Jeong SH, Ryu YB, Curtis-Long MJ et al (2009) Tyrosinase inhibitory polyphenols from roots of Morus lhou. J Agric Food Chem 57:1195–1203. https://doi.org/10.1021/jf8033286
Kim DC, Quang TH, Oh H, Kim YC (2017) Correction: Kim, D.-C,; et al. Steppogenin isolated from Cudrania tricuspidata shows antineuroinflammatory effects via NF-κB and MAPK pathways in LPS-stimulated BV2 and primary rat microglial cells. Molecules 22:2130. https://doi.org/10.3390/molecules22122130
Kinoshita D, Sakurai C, Morita M, Tsunematsu M, Hori N, Hatsuzawa K (2019) Syntaxin 11 regulates the stimulus-dependent transport of Toll-like receptor 4 to the plasma membrane by cooperating with SNAP-23 in macrophages. Mol Biol Cell 30:1085–1097. https://doi.org/10.1091/mbc.E18-10-0653
Kongkiatpaiboon S, Tungsukruthai P, Sriyakool K, Pansuksan K, Tunsirikongkon A, Pandith H (2017) Determination of Morin in Maclura cochinchinensis heartwood by HPLC. J Chromatogr Sci 55:346–350. https://doi.org/10.1093/chromsci/bmw191
Lakornwong W, Kanokmedhakul K, Masranoi J et al (2022) Cytotoxic and antibacterial xanthones from the roots of Maclura cochinchinensis. Nat Prod Res. https://doi.org/10.1080/14786419.2022.2062351
Lee JW, Kim NH, Kim JY et al (2013) Aromadendrin inhibits lipopolysaccharide-induced nuclear translocation of NF-κB and phosphorylation of JNK in RAW 264.7 macrophage cells. Biomol Ther (seoul) 21:216–221. https://doi.org/10.4062/biomolther.2013.023
Lee YJ, Kim BM, Ahn YH, Choi JH, Choi YH, Kang JL (2021) STAT6 signaling mediates PPARγ activation and resolution of acute sterile inflammation in mice. Cells 10:501. https://doi.org/10.3390/cells10030501
Lei LY, Wang RC, Pan YL et al (2021) Mangiferin inhibited neuroinflammation through regulating microglial polarization and suppressing NF-κB, NLRP3 pathway. Chin J Nat Med 19:112–119. https://doi.org/10.1016/S1875-5364(21)60012-2
Li D, Liu Q, Sun W et al (2018) 1,3,6,7-Tetrahydroxy-8-prenylxanthone ameliorates inflammatory responses resulting from the paracrine interaction of adipocytes and macrophages. Br J Pharmacol 175:1590–1606. https://doi.org/10.1111/bph.14162
Lin LL, Huang F, Chen SB et al (2005) Xanthones from the roots of Polygala caudata and their antioxidation and vasodilatation activities in vitro. Planta Med 71:372–375. https://doi.org/10.1055/s-2005-864108
Liu X, Cui C, Zhao M et al (2008) Identification of phenolics in the fruit of emblica (Phyllanthus emblica L.) and their antioxidant activities. Food Chem 109:909–915. https://doi.org/10.1016/j.foodchem.2008.01.071
Locksley HD, Murray LG (1971) Extractives from Guttiferae. Part X1X. The isolation and structure of two benzophenones, six xanthones and two biflavonoids from the heartwood of Allanblackia floribunda Oliver. J Chem Soc C. https://doi.org/10.1039/J39710001332
Ma J, Ma Y, Liu X et al (2015) Gambogic acid inhibits osteoclast formation and ovariectomy-induced osteoporosis by suppressing the JNK, p38 and Akt signalling pathways. Biochem J 469:399–408. https://doi.org/10.1042/BJ20150151
Nakashima KI, Tanaka T, Murata H, Kaburagi K, Inoue M (2015) Xanthones from the roots of Maclura cochinchinensis var. gerontogea and their retinoic acid receptor-α agonistic activity. Bioorg Med Chem Lett 25:1998–2001. https://doi.org/10.1016/j.bmcl.2015.02.075
Sato VH, Chewchinda S, Parichatikanond W, Vongsak B (2020) In vitro and in vivo evidence of hypouricemic and anti-inflammatory activities of Maclura cochinchinensis (Lour.) Corner heartwood extract. J Tradit Complement Med 10:85–94
Shibata MA, Harada-Shiba M, Shibata E et al (2019) Crude α-mangostin suppresses the development of atherosclerotic lesions in Apoe-deficient mice by a possible M2 macrophage-mediated mechanism. Int J Mol Sci 20:1722. https://doi.org/10.3390/ijms20071722
Sun J, Zhang X, Broderick M, Fein H (2003) Measurement of nitric oxide production in biological systems by using Griess reaction assay. Sensors 3:276–284. https://doi.org/10.3390/s30800276
Tabas I, Lichtman AH (2017) Monocyte-macrophages and T Cells in atherosclerosis. Immunity 47:621–634. https://doi.org/10.1016/j.immuni.2017.09.008
Termwiset P, Laohawijit N, Kasemsuk M, Department of Thai Traditional and Alternative Medicine (2015) Manual of zoning of cultivation areas for medicinal plants used in Thai traditional pharmacy. In: Termwiset P (ed) Kae Lae. Department of Thai traditional and alternative medicine, Bangkok, pp 65–67
Valentão P, Areias F, Amaral J, Andrade P, Seabra R (2000) Tetraoxygenated xanthones from Centaurium erythraea. Nat Prod Lett 14:319–323. https://doi.org/10.1080/10575630008043763
Vergadi E, Ieronymaki E, Lyroni K, Vaporidi K, Tsatsanis C (2017) Akt signaling pathway in macrophageactivation and M1/M2 polarization. J Immunol 198:1006–1014. https://doi.org/10.4049/jimmunol.1601515
Wang L, Tu YC, Lian TW, Hung JT, Yen JH, Wu MJ (2006) Distinctive antioxidant and anti-inflammatory effectsof flavonols. J Agric Food Chem 54:9798–9804
Wang D, Lou J, Ouyang C et al (2010) Ras-related protein Rab10 facilitates TLR4 signaling by promoting replenishment of TLR4 onto the plasma membrane. Proc Natl Acad Sci USA 107:13806–13811. https://doi.org/10.1073/pnas.1009428107
Wang LX, Zhang SX, Wu HJ, Rong XL, Guo J (2019a) M2b macrophage polarization and its roles in diseases. J Leukoc Biol 106:345–358. https://doi.org/10.1002/JLB.3RU1018-378RR
Wang Y, Smith W, Hao D, He B, Kong L (2019b) M1 and M2 macrophage polarization and potentially therapeutic naturally occurring compounds. Int Immunopharmacol 70:459–466. https://doi.org/10.1016/j.intimp.2019.02.050
Yu T, Gao M, Yang P et al (2019) Insulin promotes macrophage phenotype transition through PI3K/Akt and PPAR-γ signaling during diabetic wound healing. J Cell Physiol 234:4217–4231. https://doi.org/10.1002/jcp.27185
Zanoni I, Ostuni R, Marek LR et al (2011) CD14 controls the LPS-induced endocytosis of Toll-like receptor 4. Cell 147:868–880. https://doi.org/10.1016/j.cell.2011.09.051
Zhang X, Hung TM, Phuong PT et al (2006) Anti-inflammatory activity of flavonoids from Populus davidiana. Arch Pharm Res 29:1102–1108. https://doi.org/10.1007/BF02969299
Zhao X, Dai J, Xiao X et al (2014) PI3K/Akt signaling pathway modulates influenza virus induced mouse alveolar macrophage polarization to M1/M2b. PLoS ONE 9:e104506. https://doi.org/10.1371/journal.pone.0104506
Zheng XF, Hong YX, Feng GJ et al (2013) Lipopolysaccharide-induced M2 to M1 macrophage transformation for IL-12p70 production is blocked by Candida albicans mediated up-regulation of EBI3 expression. PLoS ONE 8:e63967. https://doi.org/10.1371/journal.pone.0063967
Acknowledgements
This research was supported by Thai Traditional Medical Knowledge Fund, Department of Thai Traditional and Alternative Medicine, Ministry of Public Health and the new strategic research (P2P) project of Walailak University, Nakhon Si Thammarat, Thailand. C. Jansakun expresses her gratitude to The Royal Golden Jubilee Ph.D. Program (Grant No. RGJ PHD/0216/2561). A. Suksamrarn, J. Hata, and W. Pabuprapap acknowledge partial support from the Center of Excellence for Innovation in Chemistry, Ministry of Higher Education, Science, Research, and Innovation. We would like to thank Editage (www.editage.com) for English language editing.
Funding
This research was supported by Thai Traditional Medical Knowledge Fund, Department of Thai Traditional and Alternative Medicine, Ministry of Public Health and the new strategic research (P2P) project of Walailak University, Nakhon Si Thammarat, Thailand. C. Jansakun expresses her gratitude to The Royal Golden Jubilee Ph.D. Program (Grant No. RGJ PHD/0216/2561). A. Suksamrarn, J. Hata, and W. Pabuprapap acknowledge partial support from the Center of Excellence for Innovation in Chemistry, Ministry of Higher Education, Science, Research, and Innovation.
Author information
Authors and Affiliations
Contributions
Conceptualization: CJ and WarC; methodology: CJ, WanC, TU, and WarC; validation: TU and WarC; formal analysis: CJ and OM; investigation: CJ, WanC, JH, and NS; resources: WP; data curation: CJ and WarC; writing—original draft preparation; CJ; writing—review and editing: CJ, WarC, and AS; supervision and funding acquisition: TU, WarC, and AS. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors report no conflicts of interest. There are no relevant financial or non-financial interests to disclose for the authors.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Jansakun, C., Chulrik, W., Hata, J. et al. Trihydroxyxanthones from the heartwood of Maclura cochinchinensis modulate M1/M2 macrophage polarisation and enhance surface TLR4. Inflammopharmacol 31, 529–541 (2023). https://doi.org/10.1007/s10787-022-01121-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10787-022-01121-9