Resveratrol (3, 5, 4′-Trihydroxy-trans-Stilbene) Attenuates a Mouse Model of Multiple Sclerosis by Altering the miR-124/Sphingosine Kinase 1 Axis in Encephalitogenic T Cells in the Brain

  • K. Alexa Orr Gandy
  • Jiajia Zhang
  • Prakash Nagarkatti
  • Mitzi NagarkattiEmail author


Resveratrol (3,5,4′-trihydroxy-trans-stilbene) (RES) is a naturally-derived phytoestrogen found in the skins of red grapes and berries and has potential as a novel and effective therapeutic agent. In the current study, we investigated the role of microRNA (miRNA) in RES-mediated attenuation of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Administration of RES effectively decreased disease severity, including inflammation and central nervous system immune cell infiltration. miRNA microarray analysis revealed an altered miRNA profile in encephalitogenic CD4+ T cells from EAE mice exposed to RES treatment. Additionally, bioinformatics and in silico pathway analysis suggested the involvement of RES-induced miRNA in pathways and processes that regulated cellular proliferation. Additional studies confirmed that RES affected cell cycle progression and apoptosis in activated T cells, specifically in the brain. RES treatment significantly upregulated miR-124 during EAE, while suppressing associated target gene, sphingosine kinase 1 (SK1), and this too was specific to mononuclear cells in the brains of treated mice, as peripheral immune cells remained unaltered upon RES treatment. Collectively, these studies demonstrate that RES treatment leads to amelioration of EAE development through mechanism(s) potentially involving suppression of neuroinflammation via alteration of the miR-124/SK1 axis, thereby halting cell-cycle progression and promoting apoptosis in activated encephalitogenic T cells.

Graphical Abstract

Resveratrol alters the miR-124/sphingosine kinase 1 (SK1) axis in encephalitogenic T cells, promotes cell-cycle arrest and apoptosis, and decreases neuroinflammation in experiemental autoimmune encephalomyelitis (EAE).


Experimental autoimmune encephalitis (EAE) Resveratrol (RES) CD4+ T cells microRNA 124 (miR-124) Sphingosine kinase 1 (SK1) Multiple sclerosis (MS) 



The studies were supported in part by NIH grants F32AT008539, P01AT003961, R01AT006888, R01AI123947, R01AI129788, R01MH094755, and P20GM103641.

Author Contributions

A.O.G. planned and carried out all experiments and analyses, wrote the manuscript and prepared all figures.

J.Z. performed statistical analyses when R program was employed. P.N. and M.N. supervised all work presented in this manuscript. All authors (A.O.G., J.Z., P.N., and M.N.) reviewed this manuscript.

Compliance with Ethical Standards

Competing Interests

The authors declare no financial or non-financial competing interests.

Supplementary material

11481_2019_9842_MOESM1_ESM.jpg (35 kb)
Supplemental Figure 1 Validation of microarray top up-regulated miRNAs. Brain-derived CD4+ T cells were isolated and the top five up-regulated miRNAs detected by microarray analysis were validated: miR-124, miR-132, miR-128, miR-138 and miR-127. Statistical significance was assessed using a two-tailed Student’s t test, *, *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001. n > 4 independent experiments. (JPG 35 kb)
11481_2019_9842_MOESM2_ESM.jpg (185 kb)
Supplemental Figure 2 Schematic representation of miR-124/SK1 axis in cell-cycle arrest and apoptosis. miR-124 targets SK1, preventing the production of sphingosine-1 phosphate (S1P), thus, inhibiting pro-survival and proliferative functions of S1P. Furthermore, inhibition of SK1 results in metabolic flux, leading to increased sphingosine and ceramide levels, which drive cell-cycle arrest and apoptosis. Figure adapted from (Hannun and Obeid 2008). SMase, sphingomeylinse; CDase, ceramidase; SK1, sphingosine kinase 1 (JPG 185 kb)
11481_2019_9842_MOESM3_ESM.jpg (48 kb)
Supplemental Figure 3 In vitro Resveratrol treatment does not affect miR-124 expression. Splenocytes or lymphocytes (derived from inguinal lymph nodes) were isolated from naïve or EAE + VEH mice and treated for 48 h with 2.5μg/mL Concanavalin A (ConA) or 72 h with 30μg/mL MOG. CD4+ cells were isolated and miR-124 expression was evaluated by qRT-PCR. Scale is used to enable comparison of in vitro stimulated miR-124 expression with encephalitogenic CD4+ T cells (Fig. 6a). MNE, mean normalized expression. (JPG 47 kb)


  1. Abdin AA (2013) Targeting sphingosine kinase 1 (SphK1) and apoptosis by colon-specific delivery formula of resveratrol in treatment of experimental ulcerative colitis in rats. Eur J Pharmacol 718(1–3):145–153Google Scholar
  2. Asensi M, Medina I, Ortega A, Carretero J, Baño MC, Obrador E, Estrela JM (2002) Inhibition of cancer growth by resveratrol is related to its low bioavailability. Free Radic Biol Med 33(3):387–398. Google Scholar
  3. Batoulis H et al (2011) Experimental autoimmune encephalomyelitis--achievements and prospective advances. APMIS 119(12):819–830. Google Scholar
  4. Berg J, Mahmoudjanlou Y, Duscha A, Massa MG, Thöne J, Esser C, Gold R, Haghikia A (2016) The immunomodulatory effect of laquinimod in CNS autoimmunity is mediated by the aryl hydrocarbon receptor. J Neuroimmunol 298:9–15. Google Scholar
  5. Cai H, Xie X, Ji L, Ruan X, Zheng Z (2017) Sphingosine kinase 1: a novel independent prognosis biomarker in hepatocellular carcinoma. Oncol Lett 13(4):2316–2322. Google Scholar
  6. Cao W, Dou Y, Li A (2018) Resveratrol boosts cognitive function by targeting SIRT1. Neurochem Res 43(9):1705–1713. Google Scholar
  7. Chitrala KN, Guan H, Singh NP, Busbee B, Gandy A, Mehrpouya-Bahrami P, Ganewatta MS, Tang C, Chatterjee S, Nagarkatti P, Nagarkatti M (2017) CD44 deletion leading to attenuation of experimental autoimmune encephalomyelitis results from alterations in gut microbiome in mice. Eur J Immunol 47(7):1188–1199. Google Scholar
  8. Clark PA et al (2017) Resveratrol targeting of AKT and p53 in glioblastoma and glioblastoma stem-like cells to suppress growth and infiltration. J Neurosurg 126(5):1448–1460. Google Scholar
  9. Compston A, Coles A (2002) Multiple sclerosis. Lancet 359(9313):1221–1231. Google Scholar
  10. Damsker JM, Hansen AM, Caspi RR (2010) Th1 and Th17 cells: adversaries and collaborators. Ann N Y Acad Sci 1183:211–221Google Scholar
  11. Domenis R, Cesselli D, Toffoletto B, Bourkoula E, Caponnetto F, Manini I, Beltrami AP, Ius T, Skrap M, di Loreto C, Gri G (2017) Systemic T cells immunosuppression of glioma stem cell-derived exosomes is mediated by Monocytic myeloid-derived suppressor cells. PLoS One 12(1):e0169932. Google Scholar
  12. Dong RF et al (2017) The neuroprotective role of miR-124-3p in a 6-Hydroxydopamine-induced cell model of Parkinson's disease via the regulation of ANAX5. J Cell BiochemGoogle Scholar
  13. Elliott DM, Nagarkatti M, Nagarkatti PS (2016) 3,39-Diindolylmethane ameliorates staphylococcal enterotoxin B-induced acute lung injury through alterations in the expression of MicroRNA that target apoptosis and cell-cycle arrest in activated T cells. J Pharmacol Exp Ther 357(1):177–187. Google Scholar
  14. Fayyad-Kazan H, Rouas R, Merimi M, el Zein N, Lewalle P, Jebbawi F, Mourtada M, Badran H, Ezzeddine M, Salaun B, Romero P, Burny A, Martiat P, Badran B (2010) Valproate treatment of human cord blood CD4-positive effector T cells confers on them the molecular profile (microRNA signature and FOXP3 expression) of natural regulatory CD4-positive cells through inhibition of histone deacetylase. J Biol Chem 285(27):20481–20491. Google Scholar
  15. Gandy KA, Obeid LM (2013) Regulation of the sphingosine kinase/sphingosine 1-phosphate pathway. Handb Exp Pharmacol 216:275–303Google Scholar
  16. Gao M, Chang Y, Wang X, Ban C, Zhang F (2017) Reduction of COX-2 through modulating miR-124/SPHK1 axis contributes to the antimetastatic effect of alpinumisoflavone in melanoma. Am J Transl Res 9(3):986–998Google Scholar
  17. Gault CR, Eblen ST, Neumann CA, Hannun YA, Obeid LM (2012) Oncogenic K-Ras regulates bioactive sphingolipids in a sphingosine kinase 1-dependent manner. J Biol Chem 287(38):31794–31803. Google Scholar
  18. Gautam R, Jachak SM (2009) Recent developments in anti-inflammatory natural products. Med Res Rev 29(5):767–820. Google Scholar
  19. Goldhahn K et al (2016) Antiproliferative and pro-apoptotic activities of a novel resveratrol prodrug against Jurkat CD4+ T-cells. Anticancer Res 36(2):683–689Google Scholar
  20. Gomes BAQ et al (2018) Neuroprotective mechanisms of resveratrol in Alzheimer's disease: role of SIRT1. Oxidative Med Cell Longev 2018:8152373Google Scholar
  21. Guan H, Fan D, Mrelashvili D, Hao H, Singh NP, Singh UP, Nagarkatti PS, Nagarkatti M (2013) MicroRNA let-7e is associated with the pathogenesis of experimental autoimmune encephalomyelitis. Eur J Immunol 43(1):104–114. Google Scholar
  22. Hamzei Taj S, Kho W, Aswendt M, Collmann FM, Green C, Adamczak J, Tennstaedt A, Hoehn M (2016) Dynamic modulation of microglia/macrophage polarization by miR-124 after focal cerebral ischemia. J NeuroImmune Pharmacol 11(4):733–748. Google Scholar
  23. Hanieh H, Alzahrani A (2013) MicroRNA-132 suppresses autoimmune encephalomyelitis by inducing cholinergic anti-inflammation: a new Ahr-based exploration. Eur J Immunol 43(10):2771–2782. Google Scholar
  24. Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9(2):139–150. Google Scholar
  25. Hegde VL, Tomar S, Jackson A, Rao R, Yang X, Singh UP, Singh NP, Nagarkatti PS, Nagarkatti M (2013) Distinct microRNA expression profile and targeted biological pathways in functional myeloid-derived suppressor cells induced by Delta9-tetrahydrocannabinol in vivo: regulation of CCAAT/enhancer-binding protein alpha by microRNA-690. J Biol Chem 288(52):36810–36826. Google Scholar
  26. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA (2003) Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425(6954):191–196. Google Scholar
  27. Huang TC, Chang HY, Chen CY, Wu PY, Lee H, Liao YF, Hsu WM, Huang HC, Juan HF (2011) Silencing of miR-124 induces neuroblastoma SK-N-SH cell differentiation, cell cycle arrest and apoptosis through promoting AHR. FEBS Lett 585(22):3582–3586. Google Scholar
  28. Imler TJ Jr, Petro TM (2009) Decreased severity of experimental autoimmune encephalomyelitis during resveratrol administration is associated with increased IL-17+IL-10+ T cells, CD4(−) IFN-gamma+ cells, and decreased macrophage IL-6 expression. Int Immunopharmacol 9(1):134–143. Google Scholar
  29. International Multiple Sclerosis Genetics, C et al (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476(7359):214–219. Google Scholar
  30. Jiang D, du J, Zhang X, Zhou W, Zong L, Dong C, Chen K, Chen Y, Chen X, Jiang H (2016) miR-124 promotes the neuronal differentiation of mouse inner ear neural stem cells. Int J Mol Med 38(5):1367–1376. Google Scholar
  31. Kapitonov D, Allegood JC, Mitchell C, Hait NC, Almenara JA, Adams JK, Zipkin RE, Dent P, Kordula T, Milstien S, Spiegel S (2009) Targeting sphingosine kinase 1 inhibits Akt signaling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts. Cancer Res 69(17):6915–6923. Google Scholar
  32. Kim DH, Lee YG, Park HJ, Lee JA, Kim HJ, Hwang JK, Choi JM (2015) Piceatannol inhibits effector T cell functions by suppressing TcR signaling. Int Immunopharmacol 25(2):285–292. Google Scholar
  33. Lee ST, Im W, Ban JJ, Lee M, Jung KH, Lee SK, Chu K, Kim M (2017) Exosome-based delivery of miR-124 in a Huntington's disease model. J Mov Disord 10(1):45–52. Google Scholar
  34. Lekka E, Hall J (2018) Noncoding RNAs in disease. FEBS Lett 592(17):2884–2900. Google Scholar
  35. Lim KG, Gray AI, Anthony NG, Mackay SP, Pyne S, Pyne NJ (2014) Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease. Arch Toxicol 88(12):2213–2232. Google Scholar
  36. Liu L, Zhang Q, Cai Y, Sun D, He X, Wang L, Yu D, Li X, Xiong X, Xu H, Yang Q, Fan X (2016a) Resveratrol counteracts lipopolysaccharide-induced depressive-like behaviors via enhanced hippocampal neurogenesis. Oncotarget 7(35):56045–56059Google Scholar
  37. Liu H, Gao W, Yuan J, Wu C, Yao K, Zhang L, Ma L, Zhu J, Zou Y, Ge J (2016b) Exosomes derived from dendritic cells improve cardiac function via activation of CD4(+) T lymphocytes after myocardial infarction. J Mol Cell Cardiol 91:123–133Google Scholar
  38. Mishima, T., Mizuguchi Y., Kawahigashi Y., Takizawa T., Takizawa T., RT-PCR-based analysis of microRNA (miR-1 and -124) expression in mouse CNS. Brain Res, 2007. 1131(1): p. 37–43,
  39. Muller L, Mitsuhashi M, Simms P, Gooding WE, Whiteside TL (2016) Tumor-derived exosomes regulate expression of immune function-related genes in human T cell subsets. Sci Rep 6:20254Google Scholar
  40. Pallas M et al (2013) Resveratrol: new avenues for a natural compound in neuroprotection. Curr Pharm Des 19(38):6726–6731. Google Scholar
  41. Pinto S, Cunha C, Barbosa M, Vaz AR, Brites D (2017) Exosomes from NSC-34 cells transfected with hSOD1-G93A are enriched in miR-124 and drive alterations in microglia phenotype. Front Neurosci 11:273Google Scholar
  42. Ponomarev ED, Shriver LP, Dittel BN (2006) CD40 expression by microglial cells is required for their completion of a two-step activation process during central nervous system autoimmune inflammation. J Immunol 176(3):1402–1410. Google Scholar
  43. Ponomarev ED, Maresz K, Tan Y, Dittel BN (2007) CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci 27(40):10714–10721. Google Scholar
  44. Ponomarev ED, Veremeyko T, Barteneva N, Krichevsky AM, Weiner HL (2011) MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-alpha-PU.1 pathway. Nat Med 17(1):64–70. Google Scholar
  45. Qiao W, Guo B, Zhou H, Xu W, Chen Y, Liang Y, Dong B (2017) miR-124 suppresses glioblastoma growth and potentiates chemosensitivity by inhibiting AURKA. Biochem Biophys Res Commun 486(1):43–48. Google Scholar
  46. Quoc Trung L, Espinoza JL, Takami A, Nakao S (2013) Resveratrol induces cell cycle arrest and apoptosis in malignant NK cells via JAK2/STAT3 pathway inhibition. PLoS One 8(1):e55183. Google Scholar
  47. Rege SD et al (2014) Neuroprotective effects of resveratrol in Alzheimer disease pathology. Front Aging Neurosci 6:218. Google Scholar
  48. Rieder SA, Nagarkatti P, Nagarkatti M (2012) Multiple anti-inflammatory pathways triggered by resveratrol lead to amelioration of staphylococcal enterotoxin B-induced lung injury. Br J Pharmacol 167(6):1244–1258. Google Scholar
  49. Rouse M, Singh NP, Nagarkatti PS, Nagarkatti M (2013) Indoles mitigate the development of experimental autoimmune encephalomyelitis by induction of reciprocal differentiation of regulatory T cells and Th17 cells. Br J Pharmacol 169(6):1305–1321. Google Scholar
  50. Saraiva C, Ferreira L, Bernardino L (2016) Traceable microRNA-124 loaded nanoparticles as a new promising therapeutic tool for Parkinson's disease. Neurogenesis (Austin) 3(1):e1256855Google Scholar
  51. Saud SM, Li W, Morris NL, Matter MS, Colburn NH, Kim YS, Young MR (2014) Resveratrol prevents tumorigenesis in mouse model of Kras activated sporadic colorectal cancer by suppressing oncogenic Kras expression. Carcinogenesis 35(12):2778–2786. Google Scholar
  52. Sharma S, Chopra K, Kulkarni SK, Agrewala JN (2007) Resveratrol and curcumin suppress immune response through CD28/CTLA-4 and CD80 co-stimulatory pathway. Clin Exp Immunol 147(1):155–163. Google Scholar
  53. Shindler KS, Ventura E, Rex TS, Elliott P, Rostami A (2007) SIRT1 activation confers neuroprotection in experimental optic neuritis. Invest Ophthalmol Vis Sci 48(8):3602–3609. Google Scholar
  54. Shindler KS, Ventura E, Dutt M, Elliott P, Fitzgerald DC, Rostami A (2010) Oral resveratrol reduces neuronal damage in a model of multiple sclerosis. J Neuroophthalmol 30(4):328–339Google Scholar
  55. Silber J, Lim DA, Petritsch C, Persson AI, Maunakea AK, Yu M, Vandenberg SR, Ginzinger DG, James CD, Costello JF, Bergers G, Weiss WA, Alvarez-Buylla A, Hodgson JG (2008) miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med 6:14Google Scholar
  56. Singh NP, Hegde VL, Hofseth LJ, Nagarkatti M, Nagarkatti P (2007) Resveratrol (trans-3,5,4′-trihydroxystilbene) ameliorates experimental allergic encephalomyelitis, primarily via induction of apoptosis in T cells involving activation of aryl hydrocarbon receptor and estrogen receptor. Mol Pharmacol 72(6):1508–1521. Google Scholar
  57. Singh UP, Singh NP, Singh B, Hofseth LJ, Price RL, Nagarkatti M, Nagarkatti PS (2010) Resveratrol (trans-3,5,4′-trihydroxystilbene) induces silent mating type information regulation-1 and down-regulates nuclear transcription factor-kappaB activation to abrogate dextran sulfate sodium-induced colitis. J Pharmacol Exp Ther 332(3):829–839. Google Scholar
  58. Singh NP, Singh UP, Hegde VL, Guan H, Hofseth L, Nagarkatti M, Nagarkatti PS (2011) Resveratrol (trans-3,5,4′-trihydroxystilbene) suppresses EL4 tumor growth by induction of apoptosis involving reciprocal regulation of SIRT1 and NF-kappaB. Mol Nutr Food Res 55(8):1207–1218. Google Scholar
  59. Singh NP, Singh UP, Guan H, Nagarkatti P, Nagarkatti M (2012a) Prenatal exposure to TCDD triggers significant modulation of microRNA expression profile in the thymus that affects consequent gene expression. PLoS One 7(9):e45054Google Scholar
  60. Singh UP, Singh NP, Singh B, Hofseth LJ, Taub DD, Price RL, Nagarkatti M, Nagarkatti PS (2012b) Role of resveratrol-induced CD11b(+) gr-1(+) myeloid derived suppressor cells (MDSCs) in the reduction of CXCR3(+) T cells and amelioration of chronic colitis in IL-10(−/−) mice. Brain Behav Immun 26(1):72–82Google Scholar
  61. Singh NP, Singh UP, Rouse M, Zhang J, Chatterjee S, Nagarkatti PS, Nagarkatti M (2016) Dietary indoles suppress delayed-type hypersensitivity by inducing a switch from Proinflammatory Th17 cells to anti-inflammatory regulatory T cells through regulation of MicroRNA. J Immunol 196(3):1108–1122. Google Scholar
  62. Song J, Jun M, Ahn MR, Kim OY (2016) Involvement of miR-Let7A in inflammatory response and cell survival/apoptosis regulated by resveratrol in THP-1 macrophage. Nutr Res Pract 10(4):377–384. Google Scholar
  63. Svahn AJ, Giacomotto J, Graeber MB, Rinkwitz S, Becker TS (2016) miR-124 contributes to the functional maturity of microglia. Dev Neurobiol 76(5):507–518. Google Scholar
  64. Svajger U, Obermajer N, Jeras M (2010) Dendritic cells treated with resveratrol during differentiation from monocytes gain substantial tolerogenic properties upon activation. Immunology 129(4):525–535. Google Scholar
  65. Taha TA, Kitatani K, el-Alwani M, Bielawski J, Hannun YA, Obeid LM (2006) Loss of sphingosine kinase-1 activates the intrinsic pathway of programmed cell death: modulation of sphingolipid levels and the induction of apoptosis. FASEB J 20(3):482–484. Google Scholar
  66. Thamilarasan M, Koczan D, Hecker M, Paap B, Zettl UK (2012) MicroRNAs in multiple sclerosis and experimental autoimmune encephalomyelitis. Autoimmun Rev 11(3):174–179. Google Scholar
  67. Tian H, Yu Z (2015) Resveratrol induces apoptosis of leukemia cell line K562 by modulation of sphingosine kinase-1 pathway. Int J Clin Exp Pathol 8(3):2755–2762Google Scholar
  68. Tili E, Michaille JJ, Alder H, Volinia S, Delmas D, Latruffe N, Croce CM (2010) Resveratrol modulates the levels of microRNAs targeting genes encoding tumor-suppressors and effectors of TGFbeta signaling pathway in SW480 cells. Biochem Pharmacol 80(12):2057–2065. Google Scholar
  69. Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, Reinberg D (2004) Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell 16(1):93–105. Google Scholar
  70. Venkatadri R, Muni T, Iyer AKV, Yakisich JS, Azad N (2016) Role of apoptosis-related miRNAs in resveratrol-induced breast cancer cell death. Cell Death Dis 7:e2104. Google Scholar
  71. Wang D, Li SP, Fu JS, Zhang S, Bai L, Guo L (2016) Resveratrol defends blood-brain barrier integrity in experimental autoimmune encephalomyelitis mice. J Neurophysiol 116(5):2173–2179. Google Scholar
  72. Wang C, Wei Z, Jiang G, Liu H (2017) Neuroprotective mechanisms of miR-124 activating PI3K/Akt signaling pathway in ischemic stroke. Exp Ther Med 13(6):3315–3318. Google Scholar
  73. Weiskirchen S, Weiskirchen R (2016) Resveratrol: how much wine do you have to drink to stay healthy? Adv Nutr 7(4):706–718. Google Scholar
  74. Wight RD, Tull CA, Deel MW, Stroope BL, Eubanks AG, Chavis JA, Drew PD, Hensley LL (2012) Resveratrol effects on astrocyte function: relevance to neurodegenerative diseases. Biochem Biophys Res Commun 426(1):112–115. Google Scholar
  75. Xia J, Wu Z, Yu C, He W, Zheng H, He Y, Jian W, Chen L, Zhang L, Li W (2012) miR-124 inhibits cell proliferation in gastric cancer through down-regulation of SPHK1. J Pathol 227(4):470–480. Google Scholar
  76. Xu B, Zhang Y, du XF, Li J, Zi HX, Bu JW, Yan Y, Han H, du JL (2017) Neurons secrete miR-132-containing exosomes to regulate brain vascular integrity. Cell Res 27:882–897. Google Scholar
  77. Yang X, Xu S, Qian Y, Xiao Q (2017) Resveratrol regulates microglia M1/M2 polarization via PGC-1alpha in conditions of neuroinflammatory injury. Brain Behav Immun 64:162–172. Google Scholar
  78. Yu H, Shao Y, Gao L, Zhang L, Guo K, Wu C, Hu X, Duan H (2012) Acetylation of sphingosine kinase 1 regulates cell growth and cell-cycle progression. Biochem Biophys Res Commun 417(4):1242–1247. Google Scholar
  79. Yu YH, Chen HA, Chen PS, Cheng YJ, Hsu WH, Chang YW, Chen YH, Jan Y, Hsiao M, Chang TY, Liu YH, Jeng YM, Wu CH, Huang MT, Su YH, Hung MC, Chien MH, Chen CY, Kuo ML, Su JL (2013) MiR-520h-mediated FOXC2 regulation is critical for inhibition of lung cancer progression by resveratrol. Oncogene 32(4):431–443. Google Scholar
  80. Yu A, Zhang T, Duan H, Pan Y, Zhang X, Yang G, Wang J, Deng Y, Yang Z (2017) MiR-124 contributes to M2 polarization of microglia and confers brain inflammatory protection via the C/EBP-alpha pathway in intracerebral hemorrhage. Immunol Lett 182:1–11. Google Scholar
  81. Zhang Y, Zhang M, Li X, Tang Z, Wang X, Zhong M, Suo Q, Zhang Y, Lv K (2016) Silencing MicroRNA-155 attenuates cardiac injury and dysfunction in viral myocarditis via promotion of M2 phenotype polarization of macrophages. Sci Rep 6:22613Google Scholar
  82. Zhao Y, Ling Z, Hao Y, Pang X, Han X, Califano JA, Shan L, Gu X (2017) MiR-124 acts as a tumor suppressor by inhibiting the expression of sphingosine kinase 1 and its downstream signaling in head and neck squamous cell carcinoma. Oncotarget 8(15):25005–25020. Google Scholar
  83. Zhou Y, Han Y, Zhang Z, Shi Z, Zhou L, Liu X, Jia X (2017) MicroRNA-124 upregulation inhibits proliferation and invasion of osteosarcoma cells by targeting sphingosine kinase 1. Hum Cell 30(1):30–40. Google Scholar
  84. Zielinska-Przyjemska M et al (2017) The effect of resveratrol, its naturally occurring derivatives and tannic acid on the induction of cell cycle arrest and apoptosis in rat C6 and human T98G glioma cell lines. Toxicol in Vitro 43:69–75. Google Scholar
  85. Zou T, Yang Y, Xia F, Huang A, Gao X, Fang D, Xiong S, Zhang J (2013) Resveratrol inhibits CD4+ T cell activation by enhancing the expression and activity of Sirt1. PLoS One 8(9):e75139. Google Scholar

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Authors and Affiliations

  • K. Alexa Orr Gandy
    • 1
  • Jiajia Zhang
    • 2
  • Prakash Nagarkatti
    • 1
  • Mitzi Nagarkatti
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Pathology, Microbiology and Immunology, School of MedicineUniversity of South CarolinaColumbiaUSA
  2. 2.Epidemiology and Biostatistics, Arnold School of Public HealthUniversity of South CarolinaColumbiaUSA
  3. 3.WJB Dorn VA Medical CenterColumbiaUSA

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