Curcumin Can Improve Spinal Cord Injury by Inhibiting TGF-β-SOX9 Signaling Pathway

  • Jiaying Yuan
  • Benson O. A. Botchway
  • Yong Zhang
  • Xiaoning Tan
  • Xizhi Wang
  • Xuehong LiuEmail author
Review Paper


Spinal cord injury (SCI) is a severe nervous system disease with high morbidity and disability rate. Signaling pathways play a key role in the neuronal restorative mechanism following SCI. SRY-related high mobility group (HMG)-box gene 9 (SOX9) affects glial scar formation via Transforming growth factor beta (TGF-β) signaling pathway. Activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is transferred into nucleus to upregulate TGF-β-SOX9. Curcumin exhibits potent anti-inflammatory and anti-oxidant properties. Curcumin can play an important role in SCI recovery by inhibiting the expression of NF-κB and TGF-β-SOX9. Herein, we review the potential mechanism of curcumin-inhibiting SOX9 signaling pathway in SCI treatment. The inhibition of NF-κB and SOX9 signaling pathway by curcumin has the potentiality of serving as neuronal regenerative mechanism following SCI.


Curcumin SOX9 signaling pathway NF-κB signaling pathway Spinal cord injury Neuroregeneration Anti-oxidation Anti-inflammation 


Author contributions

XL designed the study. JY, BOAB, YZ, XT, XW and XL prepared the first draft of the manuscript. JY, BOAB, YZ, and XL revised the manuscript. All authors approved the final paper.


This work was supported by the Natural Science Foundation of Zhejiang Province (No. LY19H170001) and Public Technology Applied Research Projects Foundation of Shaoxing City (No. 2017B70066).

Compliance with Ethical Standards

Conflict of interest

None to declare.


  1. Bang WS, Kim KT, Seo YJ, Cho DC, Sung JK, Kim CH (2018) Curcumin increase the expression of neural stem/progenitor cells and improves functional recovery after spinal cord injury. J Korean Neurosurg Soc 61(1):10–18. Google Scholar
  2. Bastien D, Lacroix S (2014) Cytokine pathways regulating glial and leukocyte function after spinal cord and peripheral nerve injury. Exp Neurol 258:62–77. Google Scholar
  3. Botchway BO, Moore MK, Akinleye FO, Iyer IC, Fang M (2018) Nutrition: review on the possible treatment for Alzheimer’s disease. J Alzheimers Dis 61(3):867–883. Google Scholar
  4. Brown KD, Shah MH, Liu GS, Chan EC, Crowston JG, Peshavariya HM (2017) Transforming growth factor beta1-induced NADPH oxidase-4 expression and fibrotic response in conjunctival fibroblasts. Invest Ophthalmol Vis Sci 58(7):3011–3017. Google Scholar
  5. Cekanaviciute E, Fathali N, Doyle KP, et al (2014) Astrocytic transforming growth factor-beta signaling reduces subacute neuroinflammation after stroke in mice. Glia 62(8):1227–1240. Google Scholar
  6. Chen B, Zheng M, Chen Y et al (2015) Myeloid-specific blockade of notch signaling by RBP-J knockout attenuates spinal cord injury accompanied by compromised inflammation response in mice. Mol Neurobiol 52(3):1378–1390. Google Scholar
  7. Chen J, Li X, Hu Y et al (2017) Gypenosides ameliorate carbon tetrachloride-induced liver fibrosis by inhibiting the differentiation of hepatic progenitor cells into myofibroblasts. Am J Chin Med 45(5):1061–1074. Google Scholar
  8. Chen M, Geoffroy C, Meves J et al (2018) Leucine Zipper-Bearing kinase is a critical regulator of astrocyte reactivity in the adult mammalian CNS. Cell Rep 22(13):3587–3597. Google Scholar
  9. Cheng F, Chen Y, Zhan Z et al (2018) Curc-mPEG454, a PEGylated curcumin derivative, improves anti-inflammatory and antioxidant activities: a comparative study. Inflammation 41(2):579–594. Google Scholar
  10. Choi DJ, Eun JH, Kim BG, Jou I, Park SM, Joe EH. A Parkinson’s disease gene, DJ-1, repairs brain injury through Sox9 stabilization and astrogliosis. 2018;66(2):445–458.
  11. Coricor G, Serra R (2016) TGF-β regulates phosphorylation and stabilization of Sox9 protein in chondrocytes through p38 and Smad dependent mechanisms. Sci Rep 8:6:38616. Google Scholar
  12. Dinarello CA (2009) Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 27:519–550. Google Scholar
  13. Doyle KP, Cekanaviciute E, Mamer LE, et al (2010) TGFβ signaling in the brain increases with aging and signals to astrocytes and innate immune cells in the weeks after stroke. J Neuroinflammation 7(1):62. Google Scholar
  14. Eddleston M, Mucke L (1993) Molecular profile of reactive astrocytes–implications for their role in neurologic disease. Neuroscience 54(1):15–36. Google Scholar
  15. Fan H, Zhang K, Shan L, Kuang F, Chen K, Zhu K, Ma H, Ju G, Wang YZ (2016) Reactive astrocytes undergo M1 microglia/macrohpages-induced necroptosis in spinal cord injury. Mol Neurodegener 3:11:14. Google Scholar
  16. Fan XD, Zheng HB, Fan XS, Lu S (2018) Increase of SOX9 promotes hepatic ischemia/reperfusion (IR) injury by activating TGF-β1. Biochem Biophys Res Commun 503(1):215–221. Google Scholar
  17. Fawcett JW, Asher RA (1999) The glial scar and central nervous system repair. Brain Res Bull 49(6):377–391. Google Scholar
  18. Gris P, Tighe A, Levin D, Sharma R, Brown A (2007) Transcriptional regulation of scar gene expression in primary astrocytes. Glia 15(11):1145–1155. 55)Google Scholar
  19. Ham T, Leipzig N (2018) Biomaterial strategies for limiting the impact of secondary events following spinal cord injury. Biomed Mater 13(2):024105. Google Scholar
  20. Hara M, Kobayakawa K. Interaction of reactive astrocytes with type I collagen induces astrocytic scar formation through the integrin-N-cadherin pathway after spinal cord injury. 2017;23(7):818–828.
  21. Hayta E, Elden H (2018) Acute spinal cord injury: A review of pathophysiology and potential of non-steroidal anti-inflammatory drugs for pharmacological intervention. J Chem Neuroanat 87:25–31. Google Scholar
  22. Huang L, Chen C, Zhang X et al (2018) Neuroprotective effect of curcumin against cerebral ischemia-reperfusion via mediating autophagy and inflammation. J Mol Neurosci 64(1):129–139. Google Scholar
  23. Irrera N, Arcoraci V, Mannino F et al (2018) Activation of A2A receptor by PDRN reduces neuronal damage and stimulates WNT/β-CATENIN driven neurogenesis in spinal cord injury. Front Pharmacol 9:506. eCollection 2018Google Scholar
  24. Jain N, Ayers G, Peterson E et al (2015) Traumatic spinal cord injury in the United States, 1993–2012. JAMA 313(22):2236–2243. Google Scholar
  25. Jiansheng L, Haifeng W, Suyun L, Hailong Z, Xueqing Y, Xiaoyun Z, Fengsen L, Xianmei Z, Zikai S, Yimin M, Lijun M, Yijie Z, Guojun Z, Bingxiang T (2016) Effect of sequential treatment with TCM syndrome differentiation on acute exacerbation of chronic obstructive pulmonary disease and AECOPD risk window. Complement Ther Med 29:109–115. Google Scholar
  26. Kale AD, Mane DR, Shukla D (2013) Expression of transforming growth factor β and its correlation with lipodystrophy in oral submucous fibrosis: an immunohistochemical study. Med Oral Patol Oral Cir Bucal 18(1):e12–e18. Google Scholar
  27. Kamachi Y, Cheah K, Kondoh H (1999) Mechanism of regulatory target selection by the SOX high-mobility-group domain proteins as revealed by comparison of SOX1/2/3 and SOX9. Mol Cell Biol 19(1):107–120. Google Scholar
  28. Kamachi Y, Uchikawa M, Kondoh H. Pairing (2000) SOX off: with partners in the regulation of embryonic development. Trends Genet 16(4):182–187. Google Scholar
  29. Kohta M, Kohmura E, Yamashita T (2009) Inhibition of TGF-beta1 promotes functional recovery after spinal cord injury. Neurosci Res 65(4):393–401. Google Scholar
  30. Lehmann TP, Jakub G, Harasymczuk J, Jagodziński PP (2018) Transforming growth factor β mediates communication of co-cultured human nucleus pulposus cells and mesenchymal stem cells. J Orthop Res 36(11):3023–3032. Google Scholar
  31. Li S, Gu X, Yi S. The regulatory effects of transforming growth factor-β on nerve regeneration. Cell Transpl 2017;26(3):381–394. Google Scholar
  32. Li H, Cai H, Deng J et al (2018) TGF-beta-mediated upregulation of Sox9 in fibroblast promotes renal fibrosis. Biochim Biophys Acta 1864(2):520–532. Google Scholar
  33. Lim J, Chung E, Son Y (2017) A neuropeptide, Substance-P, directly induces tissue-repairing M2 like macrophages by activating the PI3K/Akt/mTOR pathway even in the presence of IFNγ. Sci Rep 7(1):9417. Google Scholar
  34. Liu N, Xu X (2012) Neuroprotection and its molecular mechanism following spinal cord injury. Neural Regen Res 7(26):2051–2062. Google Scholar
  35. Liu X, Zhang Y, Yang Y (2018a) Therapeutic effect of curcumin and methylprednisolone in the rat spinal cord injury. Anat Rec 301(4):686. Google Scholar
  36. Liu R, Wang W, Wang S, Xie W, Li H, Ning B (2018b) microRNA-21 regulates astrocytic reaction post-acute phase of spinal cord injury through modulating TGF-β signaling. Aging (Albany NY) 10(6):1474–1488. Google Scholar
  37. Lovell-Badge R (2010) The early history of the Sox genes. Int J Biochem Cell Biol 42(3):378–380. Google Scholar
  38. Marsters CM, Rosin JM, Thornton HF, et al (2016) Oligodendrocyte development in the embryonic tuberal hypothalamus and the influence of Ascl1. Neural Dev 11(1):20. Google Scholar
  39. Martini S, Bernoth K, Main H et al (2013) A critical role for Sox9 in notch-induced astrogliogenesis and stem cell maintenance. Stem Cells 31(4):741–751. Google Scholar
  40. Mckillop WM, Dragan M, Schedl A et al (2012) Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury. Glia 61(2):164–177. Google Scholar
  41. McKillop W, York E, Rubinger L et al (2016) Conditional Sox9 ablation improves locomotor recovery after spinal cord injury by increasing reactive sprouting. Exp Neurol 283(Pt A):1–15. Google Scholar
  42. O’Neill LA (2008) The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress. Immunol Rev 226:10–18. Google Scholar
  43. Oeckinghaus A, Ghosh S (2009) The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol 1(4):a000034. Google Scholar
  44. Quiles JL, Mesa MD, Ramírez-Tortosa CL, Aguilera CM, Battino M, Gil A, Ramírez-Tortosa MC (2002) Curcuma longa extract supplementation reduces oxidative stress and attenuates aortic fatty streak development in rabbits. Arterioscler Thromb Vasc Biol 22(7):1225–1231. Google Scholar
  45. Raghavendra S, Vijayalakshmi V, Vivek V (2016) The potential of curcumin in treatment of spinal cord injury. Neurol Res Int 2016:1–11. Google Scholar
  46. Romero-Alemán Mdel M, Monzón-Mayor M, Santos E, Yanes CM (2013) Regrowth of transected retinal ganglion cell axons despite persistent astrogliosis in the lizard (Gallotia galloti). J Anat 223(1):22–37. Google Scholar
  47. Schäfer MKE, Tegeder I (2018) NG2/CSPG4 and progranulin in the posttraumatic glial scar. Matrix Biol 68–69:571–588. Google Scholar
  48. Schuliga M (2015) NF-kappaB signaling in chronic inflammatory airway disease. Biomolecules 5(3):1266–1283. Google Scholar
  49. Sharma N, Nehru B (2018) Curcumin affords neuroprotection and inhibits alpha-synuclein aggregation in lipopolysaccharide-induced Parkinson’s disease model. Inflammopharmacology 26(2):349–360. Google Scholar
  50. Shifera AS (2010) Protein-protein interactions involving IKKgamma (NEMO) that promote the activation of NF-kappaB. J Cell Physiol 223(3):558–561. Google Scholar
  51. Sun W, Cornwell A, Li J, et al (2017) SOX9 is an astrocyte-specific nuclear marker in the adult brain outside the neurogenic regions. J Neurosci 37(17):4493–4507. Google Scholar
  52. Sutherland T, Mathews K, Mao Y, Nguyen T, Gorrie C (2016) Differences in the cellular response to acute spinal cord injury between developing and mature rats highlights the potential significance of the inflammatory response. Front Cell Neurosci 10:310. Google Scholar
  53. Toda S, Miyase T, Arichi H, Tanizawa H, Takino Y (1985) Natural antioxidants. III. Antioxidative components isolated from rhizome of Curcuma longa L. Chem Pharm Bull (Tokyo) 33(4):1725–1728. Google Scholar
  54. Tsakiri N, Kimber I, Rothwell NJ, Pinteaux E (2008) Differential effects of interleukin-1 alpha and beta on interleukin-6 and chemokine synthesis in neurones. Mol Cell Neurosci 38(2):259–265. Google Scholar
  55. Wang Z, Zhou L, Zheng X et al (2017) Autophagy protects against PI3K/Akt/mTOR-mediated apoptosis of spinal cord neurons after mechanical injury. Neurosci Lett 656:158–164. Google Scholar
  56. Wang J, Pan W, Wang Y et al (2018a) Enhanced efficacy of curcumin with phosphatidylserine-decorated nanoparticles in the treatment of hepatic fibrosis. Drug Deliv 25(1):1–11. Google Scholar
  57. Wang W, Feng Y, Aimaiti Y, Jin X, Mao X, Li D (2018b) TGFβ signaling controls intrahepatic bile duct development may through regulating the Jagged1-Notch-Sox9 signaling axis. J Cell Physiol 233(8):5780–5791. Google Scholar
  58. Wang H, Song G, Chuang H, Chiu C, Abdelmaksoud A, Ye Y, Zhao L (2018c) Portrait of glial scar in neurological diseases. Int J Immunopathol Pharmacol 31:2058738418801406. Google Scholar
  59. Xia M, Zhu Y (2015) The regulation of Sox2 and Sox9 stimulated by ATP in spinal cord astrocytes. J Mol Neurosci 55(1):131–140. Google Scholar
  60. Xie W, Yang S, Zhang Q et al (2018) Knockdown of microRNA-21 promotes neurological recovery after acute spinal cord injury. Neurochem Res 43(8):1641–1649Google Scholar
  61. Xu X, Bass B, McKillop WM, Mailloux J, Liu T, Geremia NM, Hryciw T, Brown A (2018) Sox9 knockout mice have improved recovery following stroke. Exp Neurol 303:59–71. Google Scholar
  62. Xun C, Mamat M, Guo H et al (2017) Tocotrienol alleviates inflammation and oxidative stress in a rat model of spinal cord injury via suppression of transforming growth factor-beta. Exp Ther Med 14(1):431–438. Google Scholar
  63. Yang X, Chen S, Shao Z et al (2018) Apolipoprotein E deficiency exacerbates spinal cord injury in mice: inflammatory response and oxidative stress mediated by NF-κB signaling pathway. Front Cell Neurosci 12:142. Google Scholar
  64. Yu CC, Tsai LL, Wang ML et al (2013) miR145 targets the SOX9/ADAM17 axis to inhibit tumor-initiating cells and IL-6-mediated paracrine effects in head and neck cancer. Cancer Res 73(11):3425–3440. Google Scholar
  65. Yuan J, Zou M, Xiang X, Zhu H, Chu W, Liu W, Chen F, Lin J (2015) Curcumin improves neural function after spinal cord injury by the joint inhibition of the intracellular and extracellular components of glial scar. J Surg Res 195(1):235–245. Google Scholar
  66. Yuan J, Liu W, Zhu H et al (2017) Curcumin inhibits glial scar formation by suppressing astrocyte-induced inflammation and fibrosis in vitro and in vivo. Brain Res 1655:90–103. Google Scholar
  67. Zhang S, Che D, Yang F et al (2017) Tumor-associated macrophages promote tumor metastasis via the TGF-beta/SOX9 axis in non-small cell lung cancer. Oncotarget 8(59):99801–99815. Google Scholar
  68. Zhang ZB, Luo DD, Xie JH, Xian YF, Lai ZQ, Liu YH, Liu WH, Chen JN, Lai XP, Lin ZX, Su ZR (2018) Curcumin’s metabolites, tetrahydrocurcumin and octahydrocurcumin, possess superior anti-inflammatory effects in vivo through suppression of TAK1-NF-κB pathway. Front Pharmacol 9:1181. Google Scholar
  69. Zhou X, He X, Ren Y (2014) Function of microglia and macrophages in secondary damage after spinal cord injury. Neural Regen Res 9(20):1787–1795. Google Scholar
  70. Zhu F, Chong Lee Shin OLS, Pei G et al (2017) Adipose-derived mesenchymal stem cells employed exosomes to attenuate AKI-CKD transition through tubular epithelial cell dependent Sox9 activation. Oncotarget 8(41):70707–70726. Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Jiaying Yuan
    • 1
  • Benson O. A. Botchway
    • 2
  • Yong Zhang
    • 1
  • Xiaoning Tan
    • 2
  • Xizhi Wang
    • 1
  • Xuehong Liu
    • 1
    Email author
  1. 1.Department of Histology and Embryology, Medical CollegeShaoxing UniversityShaoxingChina
  2. 2.Institute of NeuroscienceZhejiang University School of MedicineHangzhouChina

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