Abstract
Tangeretin is a natural flavone found mainly in citrus peels. Although emerging evidence suggests the beneficial health effects of tangeretin, little is known about the biological role of tangeretin in the odorant-induced signal transduction pathway. In this study, the effects of tangeretin on odorant-stimulated non-neuronal 3T3-L1 cells were evaluated. Here, we present the first evidence that an olfactory receptor for lyral, an odorant, is expressed in 3T3-L1 cells and that it responds to its ligand. Stimulation with lyral increased the cyclic adenosine monophosphate (cAMP) and Ca2+ levels as well as the phosphorylation of cAMP response element binding protein (CREB). Pretreatment with tangeretin synergistically enhanced the effects of stimulation with lyral: up-regulation of cAMP and Ca2+ levels and CREB phosphorylation. These data collectively suggest that tangeretin synergistically enhances the odorant-induced signaling pathway through modulation of cAMP and CREB signal transduction in non-chemosensory cells.
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Busse D, Kudella P, Gruning NM, Gisselmann G, Stander S, Luger T, Jacobsen F, Seinstraber L, Paus R, Gkogkolou P, Bohm M, Hatt H, Benecke H (2014) A synthetic sandalwood odorant induces would-healing process in human keratinocytes via the olfactory receptor OR2AT4. J Investig Dermatol 134:2823–2832
Choi Y, Hur CG, Par T (2013) Induction of olfaction and cancer-related genes in mice fed a high-fat diet as assessed through the mode-of-action by network identification analysis. PLoS One 8:e56610
Dong Y, Cao A, Shi J, Yin P, Wang L, Ji G, Xie J, Wu D (2014) Tangeretin, a citrus polymethoxyflavonoid, induces apoptosis of human gastric cancer AGS cells through extrinsic and intrinsic signaling pathways. Oncol Rep 31:1788–1794
Fukuda N, Yomogida K, Okabe M, Touhara K (2004) Functional characterization of a mouse testicular olfactory receptor and its role in chemonsensing and regulation of sperm motility. J Cell Sci 117:5835–5845
Griffin CA, Kafadar KA, Pavlath GK (2009) MOR23 promotes muscle regeneration and regulates cell adhesion and migration. Dev Cell 17:649–661
Grosmaitre X, Vassalli A, Mombaerts P, Shepherd GM, Ma M (2006) Odorant responses of olfactory sensory neurons expressing the odorant receptor MOR23: a patch clamp analysis in gene-targeted mice. Proc Natl Acad Sci USA 103:1970–1975
Kang N, Koo J (2012) Olfactory receptors in non-chemosensory tissues. BMB Rep 45:612–622
Kim SH, Yoon YC, Kim JI, Hwang JT, Sung MJ, Kim MS, Hur HJ, Rhyu MR, Park MS, Park JH (2013) Equol (4′,7-isoflavandiol) inhibits odorant-induced cAMP and calcium levels in AGS cells expressing the olfactory receptor. Curr Top Nutraceuticals R 11:145–150
Kim SH, Yoon YC, Lee AS, Kang NN, Koo J, Rhyu MR, Park JH (2015) Expression of human olfactory receptor 10J5 in heart aorta, coronary artery, and endothelial cells and its functional role in angiogenesis. Biochem Biophys Res Commun 460:404–408
Lee AC, Tian H, Grosmaitre X, Ma M (2009) Expression patterns of odorant receptors and response properties of olfactory sensory neurons in aged mice. Chem Senses 34:695–703
Moon C, Sung YK, Reddy R, Ronnett GV (1999) Odorants induce the phosphorylation of the cAMP response element binding protein in olfactory receptor neurons. Proc Natl Acad Sci USA 96:14605–14610
Murakami A, Koshimizu K, Ohigashi H, Kuwahara S, Kuki W, Takahashi Y, Hosotani K, Kawahara S, Matsuoka Y (2002) Characteristic rat tissue accumulation of nobiletin, a chemopreventive polymethoxyflavonoid, in comparison with luteolin. BioFactors 16:73–82
Onda K, Horike N, Suzuki T, Hirano T (2013) Polymethoxyflavonoids tangeretin and nobiletin increase glucose uptake in murine adipocytes. Phytother Res 27:312–316
Pan MH, Chen WJ, Lin-Shiau SY, Ho CT, Lin JK (2002) Tnageretin induces cell-cycle G1 arrest through inhibiting cyclin-dependent kinases 2 and 4 activities as well as elevating Cdk inhibitors p21 and p27 in human colorectal carcinoma cells. Carcinogenesis 23:1677–1684
Pluznick JL, Zou DJ, Zhang X, Yan Q, Rodriguez-Gil DJ, Eisner C, Wells E, Greer CA, Wang T, Firestein S, Schnermann J, Caplan MJ (2009) Functional expression of the olfactory signaling system in the kidney. Proc Natl Acad Sci USA 106:2059–2064
Restrepo D, Teeter JH, Schild D (1996) Second messenger signaling in olfactory transduction. J Neurobiol 30:37–48
Sung MJ, Davaatseren M, Kim SH, Kim MJ, Hwang JT (2013) Boehmeria nivea attenuates LPS-induced inflammatory markers by inhibiting p38 and JNK phosphorylation in RAW264.7 macrophages. Pharm Biol 51:1131–1136
Takano K, Tabata Y, Kitao Y, Murakami R, Suzuki H, Yamada M, Iinum M, Yoneda Y, Ogawa S, Hori O (2007) Methoxyflavones protect cells against endoplasmic reticulum stress and neurotoxi. Am J Physiol Cell Physiol 292:C353–C361
Touhara K (2007) Deorphanizing vertebrate olfactory receptors: recent advances in odorant-response assays. Neurochem Int 51:132–139
Touhara K, Sengoku S, Inaki K, Tsuboi A, Hirono J, Sato T, Sakano H, Haga T (1999) Functional identification and reconstitution of an odorant receptor in single olfactory neurons. Proc Natl Acad Sci USA 96:4040–4045
Von der Heyde S, Fromm-Dornieden C, Salinas-Riester G, Beissbarth T, Baumgartner BG (2014) Dynamics of mRNA and polysomal abundance in early 3T3-L1 adipogenesis. BMC Genom 15:381
Whitman SC, Kurowska EM, Manthey JA, Daugherty A (2005) Nobiletin, a citrus flavonoid isolated from tangerines, selectively inhibits class A scavenger receptor-mediated metabolism of acetylated LDL by mouse macrophages. Atherosclerosis 178:25–32
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This study was supported by grants from the Korea Food Research Institute (E0111202-05 and E0150301-02). The authors declare that they have no conflicts of interest.
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S. H. Kim and Y. C. Yoon contributed equally to this work.
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Kim, SH., Yoon, Y.C., Hwang, JT. et al. Tangeretin synergistically enhances odorant-induced increases in cAMP and calcium levels and CREB phosphorylation in non-neuronal 3T3-L1 cells. Appl Biol Chem 59, 103–108 (2016). https://doi.org/10.1007/s13765-015-0142-7
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DOI: https://doi.org/10.1007/s13765-015-0142-7