Anti-Inflammatory Property of 5-Demethylnobiletin (5-Hydroxy-6, 7, 8, 3', 4'-pentamethoxyflavone) and Its Metabolites in Lipopolysaccharide (LPS)-Induced RAW 264.7 Cells

Overview

Journal Biology (Basel)

Publisher MDPI

Specialty Biology

Date 2022 Dec 23

PMID 36552328

Authors

Shanshan Guo

Xian Wu

Jinkai Zheng

Mingyue Song

Ping Dong

Hang Xiao

Affiliations

Soon will be listed here.

Abstract

Hydroxylated polymethoxyflavones (PMFs) are a unique class of flavonoid compounds mainly found in citrus plants. We investigated the anti-inflammatory effects of one major 5-hydroxy PMF, namely 5-demethylnobiletin (5DN) and its metabolites 5, 3'-didemethylnobiletin (M1), 5, 4'-didemethylnobiletin (M2), and 5, 3', 4'-tridemethylnobiletin (M3) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. The results showed that M2 and M3 produced stronger inhibitory effects on the production of nitric oxide (NO) than their parent compound at non-cytotoxic concentrations. Western blotting and real-time PCR analyses demonstrated that M2 and M3 significantly decreased iNOS and COX-2 gene expression. The results also showed that M1 and M3 induced heme oxygenase-1(HO-1) gene expression. Overall, our results demonstrated that metabolites of 5DN significantly inhibited LPS-induced inflammation in RAW 264.7 macrophage cells and generally possessed more potent anti-inflammatory activity than the parent compound, 5DN.

Citing Articles

Nobiletin, as a Novel PDE4B Inhibitor, Alleviates Asthma Symptoms by Activating the cAMP-PKA-CREB Signaling Pathway.

Zhang Y, Yang Y, Liang H, Liang Y, Xiong G, Lu F Int J Mol Sci. 2024; 25(19).

PMID: 39408735 PMC: 11477036. DOI: 10.3390/ijms251910406.

Study of hydrogen sulfide biosynthesis in synovial tissue from diabetes-associated osteoarthritis and its influence on macrophage phenotype and abundance.

Lendoiro-Cino N, Rodriguez-Coello A, Saborido A, F-Burguera E, Fernandez-Rodriguez J, Meijide-Failde R J Physiol Biochem. 2023; 79(3):653-667.

PMID: 37335394 PMC: 10338594. DOI: 10.1007/s13105-023-00968-y.

References

Li S, Lambros T, Wang Z, Goodnow R, Ho C . Efficient and scalable method in isolation of polymethoxyflavones from orange peel extract by supercritical fluid chromatography. J Chromatogr B Analyt Technol Biomed Life Sci. 2006; 846(1-2):291-7. DOI: 10.1016/j.jchromb.2006.09.010. View

Wink M . Evolutionary advantage and molecular modes of action of multi-component mixtures used in phytomedicine. Curr Drug Metab. 2008; 9(10):996-1009. DOI: 10.2174/138920008786927794. View

Qiu P, Dong P, Guan H, Li S, Ho C, Pan M . Inhibitory effects of 5-hydroxy polymethoxyflavones on colon cancer cells. Mol Nutr Food Res. 2010; 54 Suppl 2:S244-52. DOI: 10.1002/mnfr.200900605. View

Li S, Sang S, Pan M, Lai C, Lo C, Yang C . Anti-inflammatory property of the urinary metabolites of nobiletin in mouse. Bioorg Med Chem Lett. 2007; 17(18):5177-81. DOI: 10.1016/j.bmcl.2007.06.096. View

Murakami A, Shigemori T, Ohigashi H . Zingiberaceous and citrus constituents, 1'-acetoxychavicol acetate, zerumbone, auraptene, and nobiletin, suppress lipopolysaccharide-induced cyclooxygenase-2 expression in RAW264.7 murine macrophages through different modes of action. J Nutr. 2005; 135(12 Suppl):2987S-2992S. DOI: 10.1093/jn/135.12.2987S. View

Chen X, Kunsch C . Induction of cytoprotective genes through Nrf2/antioxidant response element pathway: a new therapeutic approach for the treatment of inflammatory diseases. Curr Pharm Des. 2004; 10(8):879-91. DOI: 10.2174/1381612043452901. View

Lee T, Chau L . Heme oxygenase-1 mediates the anti-inflammatory effect of interleukin-10 in mice. Nat Med. 2002; 8(3):240-6. DOI: 10.1038/nm0302-240. View

Coussens L, Werb Z . Inflammation and cancer. Nature. 2002; 420(6917):860-7. PMC: 2803035. DOI: 10.1038/nature01322. View

Syapin P . Regulation of haeme oxygenase-1 for treatment of neuroinflammation and brain disorders. Br J Pharmacol. 2008; 155(5):623-40. PMC: 2584924. DOI: 10.1038/bjp.2008.342. View

10.

Jeon W, Kim B . WITHDRAWN: Heme oxygenase-1 mediates the anti-inflammatory effect of propyl gallate in LPS-stimulated macrophages. Biochem Biophys Res Commun. 2007; 361(3):645-650. DOI: 10.1016/j.bbrc.2007.07.056. View

11.

Wu X, Li Z, Sun Y, Li F, Gao Z, Zheng J . Identification of Xanthomicrol as a Major Metabolite of 5-Demethyltangeretin in Mouse Gastrointestinal Tract and Its Inhibitory Effects on Colon Cancer Cells. Front Nutr. 2020; 7:103. PMC: 7405597. DOI: 10.3389/fnut.2020.00103. View

12.

Tang M, Ogawa K, Asamoto M, Hokaiwado N, Seeni A, Suzuki S . Protective effects of citrus nobiletin and auraptene in transgenic rats developing adenocarcinoma of the prostate (TRAP) and human prostate carcinoma cells. Cancer Sci. 2007; 98(4):471-7. PMC: 11158555. DOI: 10.1111/j.1349-7006.2007.00417.x. View

13.

Li S, Pan M, Lai C, Lo C, Dushenkov S, Ho C . Isolation and syntheses of polymethoxyflavones and hydroxylated polymethoxyflavones as inhibitors of HL-60 cell lines. Bioorg Med Chem. 2007; 15(10):3381-9. DOI: 10.1016/j.bmc.2007.03.021. View

14.

Bas E, Recio M, Giner R, Manez S, Cerda-Nicolas M, Rios J . Anti-inflammatory activity of 5-O-demethylnobiletin, a polymethoxyflavone isolated from Sideritis tragoriganum. Planta Med. 2006; 72(2):136-42. DOI: 10.1055/s-2005-873191. View

15.

Mora A, Paya M, Rios J, Alcaraz M . Structure-activity relationships of polymethoxyflavones and other flavonoids as inhibitors of non-enzymic lipid peroxidation. Biochem Pharmacol. 1990; 40(4):793-7. DOI: 10.1016/0006-2952(90)90317-e. View

16.

Fushiya S, Kishi Y, Hattori K, Batkhuu J, Takano F, Singab A . Flavonoids from Cleome droserifolia suppress NO production in activated macrophages in vitro. Planta Med. 1999; 65(5):404-7. DOI: 10.1055/s-1999-14084. View

17.

Lin W, Karin M . A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest. 2007; 117(5):1175-83. PMC: 1857251. DOI: 10.1172/JCI31537. View

18.

Campbell N, Fitzgerald H, Dunne A . Regulation of inflammation by the antioxidant haem oxygenase 1. Nat Rev Immunol. 2021; 21(7):411-425. DOI: 10.1038/s41577-020-00491-x. View

19.

Pan M, Lai C, Wang Y, Ho C . Acacetin suppressed LPS-induced up-expression of iNOS and COX-2 in murine macrophages and TPA-induced tumor promotion in mice. Biochem Pharmacol. 2006; 72(10):1293-303. DOI: 10.1016/j.bcp.2006.07.039. View

20.

Saito T, Abe D, Sekiya K . Nobiletin enhances differentiation and lipolysis of 3T3-L1 adipocytes. Biochem Biophys Res Commun. 2007; 357(2):371-6. DOI: 10.1016/j.bbrc.2007.03.169. View