Inflammation Research

, Volume 68, Issue 4, pp 297–310 | Cite as

Artemisinin and its derivatives: a potential therapeutic approach for oral lichen planus

  • Rui-Jie Ma
  • Ming-Jing He
  • Ya-Qin Tan
  • Gang ZhouEmail author
Original Research Paper



Oral lichen planus (OLP) is a common T-cell-mediated oral mucosal disease, whose pathogenesis mainly includes antigen-specific and non-specific mechanisms. As a refractory chronic inflammatory disease, there is still no curable management for OLP till now.


Artemisinins are a family of compounds that are widely used as frontline treatment for malaria worldwide. In addition to its well-established antimalarial properties, emerging evidence hints that artemisinin family drugs also possess preferential immunoregulatory and anti-inflammation properties, such as modifying T lymphocytes’ activation and cytokines release, modulating Th1/Th2 balance, activating regulatory T cells (Tregs), modulating inflammatory signaling pathways, as well as acting on non-specific mechanisms of OLP. However, there is still no report focused on the influence of artemisinins on OLP.


This review outlined the data-based immunomodulatory effects of artemisinins on different immune cells in conjunction with their therapeutic prospective with regard to the pathogenesis of OLP, suggesting that artemisinin and its derivatives might be possible candidates for treatment of OLP.


Oral lichen planus Artemisinins Autoimmune disease Pathogenesis Treatment 



Oral lichen planus


Systemic lupus erythematosus


Transforming growth factorβ


Protein kinase B


Matrix metalloproteinase


Collagen-induced arthritis


Nuclear factor-kappa B


Mitogen-activated protein kinase


Mammalian target of rapamycin


C–C chemokine receptor


C–X–C chemokine receptor


Reactive oxygen species





This work was supported by grants from National Natural Science Foundation of China (No. 81771080, No. 81371147) to Professor Zhou Gang.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. 1.
    Alrashdan MS, Cirillo N, McCullough M. Oral lichen planus: a literature review and update. Arch Dermatol Res. 2016;308(8):539–51. Scholar
  2. 2.
    van der Waal I. Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of management. Oral Oncol. 2009;45(4–5):317–23. Scholar
  3. 3.
    Aghbari SMH, Abushouk AI, Attia A, Elmaraezy A, Menshawy A, Ahmed MS, et al. Malignant transformation of oral lichen planus and oral lichenoid lesions: a meta-analysis of 20095 patient data. Oral Oncol. 2017;68:92–102. Scholar
  4. 4.
    Payeras MR, Cherubini K, Figueiredo MA, Salum FG. Oral lichen planus: focus on etiopathogenesis. Arch Oral Biol. 2013;58(9):1057–69. Scholar
  5. 5.
    Roopashree MR, Gondhalekar RV, Shashikanth MC, George J, Thippeswamy SH, Shukla A. Pathogenesis of oral lichen planus—a review. J Oral Pathol Med. 2010;39(10):729–34. Scholar
  6. 6.
    Nogueira PA, Carneiro S, Ramos-e-Silva M. Oral lichen planus: an update on its pathogenesis. Int J Dermatol. 2015;54(9):1005–10.PubMedCrossRefGoogle Scholar
  7. 7.
    Rubaci AH, Kazancioglu HO, Olgac V, Ak G. The roles of matrix metalloproteinases-2, -7, -10 and tissue inhibitor of metalloproteinase-1 in the pathogenesis of oral lichen planus. J Oral Pathol Med. 2012;41(9):689–96. Scholar
  8. 8.
    Zhang N, Zhang J, Tan YQ, Du GF, Lu R, Zhou G. Activated Akt/mTOR-autophagy in local T cells of oral lichen planus. Int Immunopharmacol. 2017;48:84–90. Scholar
  9. 9.
    Yang JG, Sun YR, Chen GY, Liang XY, Zhang J, Zhou G. Different expression of MicroRNA-146a in peripheral blood CD4(+) T cells and lesions of oral lichen planus. Inflammation. 2016;39(2):860–6. Scholar
  10. 10.
    Tan YQ, Zhang J, Du GF, Lu R, Chen GY, Zhou G. Altered autophagy-associated genes expression in T cells of oral lichen planus correlated with clinical features. Mediators Inflamm. 2016;2016:4867368.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Zhou G, Xia K, Du GF, Chen XM, Xu XY, Lu R, et al. Activation of nuclear factor-kappa B correlates with tumor necrosis factor-alpha in oral lichen planus: a clinicopathologic study in atrophic-erosive and reticular form. J Oral Pathol Med. 2009;38(7):559–64. Scholar
  12. 12.
    Hu JY, Zhang J, Ma JZ, Liang XY, Chen GY, Lu R, et al. MicroRNA-155-IFN-γ feedback loop in CD4(+)T cells of erosive type oral lichen planus. Sci Rep. 2015;5:16935. Scholar
  13. 13.
    Wang JX, Tang W, Shi LP, Wan J, Zhou R, Ni J, et al. Investigation of the immunosuppressive activity of artemether on T-cell activation and proliferation. Br J Pharmacol. 2007;150(5):652–61. Scholar
  14. 14.
    Hou L, Huang H. Immune suppressive properties of artemisinin family drugs. Pharmacol Ther. 2016;166:123–7. Scholar
  15. 15.
    Li Y. Qinghaosu (artemisinin): chemistry and pharmacology. Acta Pharmacol Sin. 2012;33(9):1141–6. Scholar
  16. 16.
    Zhao D, Zhang J, Xu G, Wang Q. Artesunate protects LPS-induced acute lung injury by inhibiting TLR4 expression and inducing Nrf2 activation. Inflammation. 2017;40(3):798–805. Scholar
  17. 17.
    Dong F, Zhou X, Li C, Yan S, Deng X, Cao Z, et al. Dihydroartemisinin targets VEGFR2 via the NF-κB pathway in endothelial cells to inhibit angiogenesis. Cancer Biol Therapy. 2014;15(11):1479–88.CrossRefGoogle Scholar
  18. 18.
    Hou LF, He SJ, Wang JX, Yang Y, Zhu FH, Zhou Y, et al. SM934, a water-soluble derivative of arteminisin, exerts immunosuppressive functions in vitro and in vivo. Int Immunopharmacol. 2009;9(13–14):1509–17.PubMedCrossRefGoogle Scholar
  19. 19.
    Wang JX, Hou LF, Yang Y, Tang W, Li Y, Zuo JP. SM905, an artemisinin derivative, inhibited NO and pro-inflammatory cytokine production by suppressing MAPK and NF-kappaB pathways in RAW 264.7 macrophages. Acta Pharmacol Sin. 2009;30(10):1428–35. Scholar
  20. 20.
    Yang ZS, Zhou WL, Sui Y, Wang JX, Wu JM, Zhou Y, et al. Synthesis and immunosuppressive activity of new artemisinin derivatives. 1. [12(beta or alpha)-dihydroartemisininoxy]phen(ox)yl aliphatic acids and esters. J Med Chem. 2005;48(14):4608–17. Scholar
  21. 21.
    Yang ZS, Wang JX, Zhou Y, Zuo JP, Li Y. Synthesis and immunosuppressive activity of new artemisinin derivatives. Part 2: 2-[12(beta or alpha)-dihydroartemisinoxymethyl(or 1′-ethyl)]phenoxyl propionic acids and esters. Bioorganic Med Chem. 2006;14(23):8043–9. Scholar
  22. 22.
    Zhou W-l, Wu J-m, Wu Q-l, Wang J-x, Zhou Y, Zhou R, et al. A novel artemisinin derivative, 3-(12-β-artemisininoxy) phenoxyl succinic acid (SM735), mediates immunosuppressive effects in vitro and in vivo. Acta Pharmacol Sin. 2005;26:1352. Scholar
  23. 23.
    Lee SH, Cho YC, Kim KH, Lee IS, Choi HJ, Kang BY. Artesunate inhibits proliferation of naı ¨ve CD4(+) T cells but enhances function of effector T cells. Arch Pharm Res. 2015;38(6):1195–203.PubMedCrossRefGoogle Scholar
  24. 24.
    Lin ZM, Yang XQ, Zhu FH, He SJ, Tang W, Zuo JP. Artemisinin analogue SM934 attenuate collagen-induced arthritis by suppressing T follicular helper cells and T helper 17 cells. Sci Rep. 2016;6:38115. Scholar
  25. 25.
    Magenta D, Sangiovanni E, Basilico N, Haynes RK, Parapini S, Colombo E, et al. Inhibition of metalloproteinase-9 secretion and gene expression by artemisinin derivatives. Acta Trop. 2014;140:77–83. Scholar
  26. 26.
    Li X, Li TT, Zhang XH, Hou LF, Yang XQ, Zhu FH, et al. Artemisinin analogue SM934 ameliorates murine experimental autoimmune encephalomyelitis through enhancing the expansion and functions of regulatory T cell. PLoS One. 2013;8(8):e74108. Scholar
  27. 27.
    Li H, Zuo J, Tang W. Water-soluble artemisinin derivatives as promising therapeutic immunosuppressants of autoimmune diseases. Cell Mol Immunol. 2017;14(11):887–9. Scholar
  28. 28.
    Raffetin A, Bruneel F, Roussel C, Thellier M, Buffet P, Caumes E, et al. Use of artesunate in non-malarial indications. Med et Maladies Infectieuses. 2018;48(4):238–49. Scholar
  29. 29.
    Schepetkin IA, Kirpotina LN, Mitchell PT, Kishkentaeva §¡ S, Shaimerdenova ZR, Atazhanova GA, et al. The natural sesquiterpene lactones arglabin, grosheimin, agracin, parthenolide, and estafiatin inhibit T cell receptor (TCR) activation. Phytochemistry. 2018;146:36–46. Scholar
  30. 30.
    Kong LY, Tan RX. Artemisinin, a miracle of traditional Chinese medicine. Nat Prod Rep. 2015;32(12):1617–21. Scholar
  31. 31.
    Barnett DS, Guy RK. Antimalarials in development in 2014. Chem Rev. 2014;114(22):11221–41. Scholar
  32. 32.
    An J, Minie M, Sasaki T, Woodward JJ, Elkon KB. Antimalarial drugs as immune modulators: new mechanisms for old drugs. Ann Rev Med. 2017;68:317–30. Scholar
  33. 33.
    Ho WE, Peh HY, Chan TK, Wong WS. Artemisinins: pharmacological actions beyond anti-malarial. Pharmacol Ther. 2014;142(1):126–39. Scholar
  34. 34.
    Kim WS, Choi WJ, Lee S, Kim WJ, Lee DC, Sohn UD, et al. Anti-inflammatory, antioxidant and antimicrobial effects of artemisinin extracts from Artemisia annua L. Korean J Physiol Pharmacol. 2015;19(1):21–7. Scholar
  35. 35.
    Chaturvedi D, Goswami A, Pratim Saikia P, Barua NC, Rao PG. Artemisinin and its derivatives: a novel class of anti-malarial and anti-cancer agents. Chem Soc Rev. 2010;39(2):435–54. Scholar
  36. 36.
    Cui L, Su X-z. Discovery, mechanisms of action and combination therapy of artemisinin. Expert Rev Anti Infect Therapy. 2009;7(8):999–1013. Scholar
  37. 37.
    Wang JX, Tang W, Yang ZS, Wan J, Shi LP, Zhang Y, et al. Suppressive effect of a novel water-soluble artemisinin derivative SM905 on T cell activation and proliferation in vitro and in vivo. Eur J Pharmacol. 2007;564(1–3):211–8. Scholar
  38. 38.
    Li TT, Zhang XH, Jing JF, Li X, Yang XQ, Zhu FH, et al. Artemisinin analogue SM934 ameliorates the proteinuria and renal fibrosis in rat experimental membranous nephropathy. Acta Pharmacol Sin. 2015;36(2):188–99. Scholar
  39. 39.
    Wang H, Zhang D, Han Q, Zhao X, Zeng X, Xu Y, et al. Role of distinct CD4(+) T helper subset in pathogenesis of oral lichen planus. J Oral Pathol Med. 2016;45(6):385–93. Scholar
  40. 40.
    Li T, Chen H, Yang Z, Liu XG, Zhang LM, Wang H. Evaluation of the immunosuppressive activity of artesunate in vitro and in vivo. Int Immunopharmacol. 2013;16(2):306–12.PubMedCrossRefGoogle Scholar
  41. 41.
    Zhao YG, Wang Y, Guo Z, Gu AD, Dan HC, Baldwin AS, et al. Dihydroartemisinin ameliorates inflammatory disease by its reciprocal effects on Th and regulatory T cell function via modulating the mammalian target of rapamycin pathway. J Immunol. 2012;189(9):4417–25. Scholar
  42. 42.
    Hou LF, He SJ, Li X, Wan CP, Yang Y, Zhang XH, et al. SM934 treated lupus-prone NZB6NZW F1 mice by enhancing macrophage interleukin-10 production and suppressing pathogenic T cell development. PLoS One. 2012;7(2):e32424.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Tan YQ, Li Q, Zhang J, Du GF, Lu R, Zhou G. Increased circulating CXCR5(+) CD4(+) T follicular helper-like cells in oral lichen planus. J Oral Pathol Med. 2017;46(9):803–9. Scholar
  44. 44.
    Lu R, Zhou G, Du G, Xu X, Yang J, Hu J. Expression of T-bet and GATA-3 in peripheral blood mononuclear cells of patients with oral lichen planus. Arch Oral Biol. 2011;56(5):499–505. Scholar
  45. 45.
    Piccinni MP, Lombardelli L, Logiodice F, Tesi D, Kullolli O, Biagiotti R, et al. Potential pathogenetic role of Th17, Th0, and Th2 cells in erosive and reticular oral lichen planus. Oral Dis. 2014;20(2):212–8. Scholar
  46. 46.
    Lu R, Zeng X, Han Q, Lin M, Long L, Dan H, et al. Overexpression and selectively regulatory roles of IL-23/IL-17 axis in the lesions of oral lichen planus. Mediators Inflamm. 2014;2014:701094. Scholar
  47. 47.
    Liu H, Tian Q, Ai X, Qin Y, Cui Z, Li M, et al. Dihydroartemisinin attenuates autoimmune thyroiditis by inhibiting the CXCR3/PI3K/AKT/NF-kappaB signaling pathway. Oncotarget. 2017;8(70):115028–40. Scholar
  48. 48.
    Wei M, Xie X, Chu X, Yang X, Guan M, Wang D. Dihydroartemisinin suppresses ovalbumin-induced airway inflammation in a mouse allergic asthma model. Immunopharmacol Immunotoxicol. 2013;35(3):382–9. Scholar
  49. 49.
    Wang H, Han Q, Luo Z, Xu C, Liu J, Dan H, et al. Oral lichen planus may enhance the expression of Th17-associated cytokines in local lesions of chronic periodontitis. Clin Oral Investig. 2014;18(6):1647–54.PubMedCrossRefGoogle Scholar
  50. 50.
    Zhu S, Qian Y. IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential. Clin Sci. 2012;122(11–12):487–511. Scholar
  51. 51.
    Shen Z, Gao X, Ma L, Zhou Z, Shen X, Liu W. Expression of Foxp3 and interleukin-17 in lichen planus lesions with emphasis on difference in oral and cutaneous variants. Arch Dermatol Res. 2014;306(5):441–6. Scholar
  52. 52.
    Liu J, Hong X, Lin D, Luo X, Zhu M, Mo H. Artesunate influences Th17/Treg lymphocyte balance by modulating Treg apoptosis and Th17 proliferation in a murine model of rheumatoid arthritis. Exp Ther Med. 2017;13(5):2267–73. Scholar
  53. 53.
    Li T, Chen H, Wei N, Mei X, Zhang S, Liu DL, et al. Anti-inflammatory and immunomodulatory mechanisms of artemisinin on contact hypersensitivity. Int Immunopharmacol. 2012;12(1):144–50.PubMedCrossRefGoogle Scholar
  54. 54.
    Hou LF, He SJ, Li X, Yang Y, He PL, Zhou Y, et al. Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses. Arthritis Rheum. 2011;63(8):2445–55. Scholar
  55. 55.
    Wang JX, Tang W, Zhou R, Wan J, Shi LP, Zhang Y, et al. The new water-soluble artemisinin derivative SM905 ameliorates collagen-induced arthritis by suppression of inflammatory and Th17 responses. Br J Pharmacol. 2008;153(6):1303–10. Scholar
  56. 56.
    Liu X, Chen X, Zhong B, Wang A, Wang X, Chu F, et al. Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature. 2014;507(7493):513–8. Scholar
  57. 57.
    Schmidt A, Oberle N, Krammer P. Molecular mechanisms of treg-mediated T cell suppression. Front Immunol. 2012;3:51. Scholar
  58. 58.
    Firth FA, Friedlander LT, Parachuru VP, Kardos TB, Seymour GJ, Rich AM. Regulation of immune cells in oral lichen planus. Arch Dermatol Res. 2015;307(4):333–9. Scholar
  59. 59.
    Pollizzi KN, Powell JD. Regulation of T cells by mTOR: the known knowns and the known unknowns. Trends Immunol. 2015;36(1):13–20. Scholar
  60. 60.
    Tao XA, Xia J, Chen XB, Wang H, Dai YH, Rhodus NL, et al. FOXP3 T regulatory cells in lesions of oral lichen planus correlated with disease activity. Oral Dis. 2010;16(1):76–82. Scholar
  61. 61.
    Zhou L, Cao T, Wang Y, Yao H, Du G, Chen G, et al. Frequently increased but functionally impaired CD4+ CD25+ regulatory T cells in patients with oral lichen planus. Inflammation. 2016;39(3):1205–15. Scholar
  62. 62.
    Lei L, Zhan L, Tan W, Chen S, Li Y, Reynolds M. Foxp3 gene expression in oral lichen planus: a clinicopathological study. Mol Med Rep. 2014;9(3):928–34. Scholar
  63. 63.
    Josefowicz S, Lu L, Rudensky A. Regulatory T. cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012;30:531–64. Scholar
  64. 64.
    Miraghazadeh B, Cook MC. Nuclear factor-kappaB in autoimmunity: man and mouse. Front Immunol. 2018;9:613. Scholar
  65. 65.
    Sun S. The non-canonical NF-κB pathway in immunity and inflammation. Nat Rev Immunol. 2017;17(9):545–58. Scholar
  66. 66.
    Janardhanam S, Prakasam S, Swaminathan V, Kodumudi K, Zunt S, Srinivasan M. Differential expression of TLR-2 and TLR-4 in the epithelial cells in oral lichen planus. Arch Oral Biol. 2012;57(5):495–502. Scholar
  67. 67.
    Wang Y, Huang Z, Wang L, Meng S, Fan Y, Chen T, et al. The anti-malarial artemisinin inhibits pro-inflammatory cytokines via the NF-κB canonical signaling pathway in PMA-induced THP-1 monocytes. Int J Mol Med. 2011;27(2):233–41.PubMedCrossRefGoogle Scholar
  68. 68.
    Wang YUE, Cao J, Fan Y, Xie Y, Xu Z, Yin Z, et al. Artemisinin inhibits monocyte adhesion to HUVECs through the NF-κB and MAPK pathways in vitro. Int J Mol Med. 2016;37(6):1567–75. Scholar
  69. 69.
    Yu L, Chen JF, Shuai X, Xu Y, Ding Y, Zhang J, et al. Artesunate protects pancreatic beta cells against cytokine-induced damage via SIRT1 inhibiting NF-κB activation. J Endocrinol Invest. 2016;39(1):83–91. Scholar
  70. 70.
    Cao Q, Jiang Y, Shi J, Xu C, Liu X, Yang T, et al. Artemisinin inhibits the proliferation, migration, and inflammatory reaction induced by tumor necrosis factor-α in vascular smooth muscle cells through nuclear factor kappa B pathway. J Surg Res. 2015;194(2):667–78.PubMedCrossRefGoogle Scholar
  71. 71.
    Gu Y, Wang X, Wang X, Yuan M, Wu G, Hu J, et al. Artemisinin attenuates post-infarct myocardial remodeling by down-regulating the NF-κB pathway. Tohoku J Exp Med. 2012;227(3):161–70.PubMedCrossRefGoogle Scholar
  72. 72.
    Shi JQ, Zhang CC, Sun XL, Cheng XX, Wang JB, Zhang YD, et al. Antimalarial drug artemisinin extenuates amyloidogenesis and neuroinflammation in APPswe/PS1dE9 transgenic mice via inhibition of nuclear factor-kappaB and NLRP3 inflammasome activation. CNS Neurosci Ther. 2013;19(4):262–8. Scholar
  73. 73.
    Wang D, Shi J, Lv S, Xu W, Li J, Ge W, et al. Artesunate attenuates lipopolysaccharide-stimulated proinflammatory responses by suppressing TLR4, MyD88 expression, and NF-kB activation in microglial cells. Inflammation. 2015;38(5):1925–32.PubMedCrossRefGoogle Scholar
  74. 74.
    Zhao X, Liu M, Li J, Yin S, Wu Y, Wang A. Antimalarial agent artesunate protects concanavalin A-induced autoimmune hepatitis in mice by inhibiting inflammatory responses. Chem Biol Interact. 2017;274:116–23. Scholar
  75. 75.
    Okorji UP, Olajide OA. A semi-synthetic derivative of artemisinin, artesunate inhibits prostaglandin E2 production in LPS/IFNγ-activated BV2 microglia. Bioorganic Med Chem. 2014;22(17):4726–34.CrossRefGoogle Scholar
  76. 76.
    Lai L, Chen Y, Tian X, Li X, Zhang X, Lei J, et al. Artesunate alleviates hepatic fibrosis induced by multiple pathogenic factors and inflammation through the inhibition of LPS/TLR4/NF-kB signaling pathway in rats. Eur J Pharmacol. 2015;765:234–41.PubMedCrossRefGoogle Scholar
  77. 77.
    Huang X, Xie Z, Liu F, Han C, Zhang D, Wang D, et al. Dihydroartemisinin inhibits activation of the Toll-like receptor 4 signaling pathway and production of type I interferon in spleen cells from lupus-prone MRL/lpr mice. Int Immunopharmacol. 2014;22(1):266–72. Scholar
  78. 78.
    Wan RJ, Li YH. Effects of Artesunate prevent nephritis via the Toll–like receptor 4/nuclear factor–κB signaling pathway in rats. Mol Med Rep. 2017;16(5):6389–95. Scholar
  79. 79.
    Yang Z, Ding J, Yang C, Gao Y, Li X, Chen X, et al. Immunomodulatory and anti-inflammatory properties of artesunate in experimental colitis. Curr Med Chem. 2012;19(26):4541–51. Scholar
  80. 80.
    Lee Y, Kim YJ, Kim MH, Kwak JM. MAPK cascades in guard cell signal transduction. Front Plant Sci. 2016;7(154):80. Scholar
  81. 81.
    Arthur J, Ley S. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol. 2013;13(9):679–92. Scholar
  82. 82.
    Du G, Chen J, Wang Y, Cao T, Zhou L, Wang Y, et al. Differential expression of STAT-3 in subtypes of oral lichen planus: a preliminary study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2018;125(3):236 – 43.e1. Scholar
  83. 83.
    Wang K, Li J, Wang Z, Mi C, Ma J, Piao L, et al. Artemisinin inhibits inflammatory response via regulating NF-κB and MAPK signaling pathways. Immunopharmacol Immunotoxicol. 2017;39(1):28–36. Scholar
  84. 84.
    Wang Y, Huang ZQ, Wang CQ, Wang LS, Meng S, Zhang YC, et al. Artemisinin inhibits extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase-9 expression via a protein kinase Cδ/p38/extracellular signal-regulated kinase pathway in phorbol myristate acetate-induced THP-1 macrophages. Clin Exp Pharmacol Physiol. 2011;38(1):11–8.PubMedCrossRefGoogle Scholar
  85. 85.
    He Y, Fan J, Lin H, Yang X, Ye Y, Liang L, et al. The anti-malaria agent artesunate inhibits expression of vascular endothelial growth factor and hypoxia-inducible factor-1α in human rheumatoid arthritis fibroblast-like synoviocyte. Rheumatol Int. 2011;31(1):53–60.PubMedCrossRefGoogle Scholar
  86. 86.
    Cheng C, Ho WE, Goh FY, Guan SP, Kong LR, Lai WQ, et al. Anti-malarial drug artesunate attenuates experimental allergic asthma via inhibition of the phosphoinositide 3-kinase/Akt pathway. PLoS One. 2011;6(6):e20932. Scholar
  87. 87.
    Merry R, Belfield L, McArdle P, McLennan A, Crean S, Foey A. Oral health and pathology: a macrophage account. Br J Oral Maxillofac Surg. 2012;50(1):2–7. Scholar
  88. 88.
    Vered M, F¨¹rth E, Shalev Y, Dayan D. Inflammatory cells of immunosuppressive phenotypes in oral lichen planus have a proinflammatory pattern of expression and are associated with clinical parameters. Clin Oral Invest. 2013;17(5):1365–73. Scholar
  89. 89.
    Kim HG, Yang JH, Han EH, Choi JH, Khanal T, Jeong MH, et al. Inhibitory effect of dihydroartemisinin against phorbol ester-induced cyclooxygenase-2 expression in macrophages. Food Chem Toxicol. 2013;56:93–9. Scholar
  90. 90.
    Park KH, Yoon YD, Han SB, Oh SJ, Yun J, Lee CW, et al. Artemisinin inhibits lipopolysaccharide-induced interferon-β production in RAW 264.7 cells: implications on signal transducer and activator of transcription-1 signaling and nitric oxide production. Int Immunopharmacol. 2012;14(4):580–4.PubMedCrossRefGoogle Scholar
  91. 91.
    Zhou XJ, Sugerman PB, Savage NW, Walsh LJ. Matrix metalloproteinases and their inhibitors in oral lichen planus. J Cutan Pathol. 2001;28(2):72–82. Scholar
  92. 92.
    Chen Y, Zhang W, Geng N, Tian K, Jack Windsor L, MMPs. TIMP-2, and TGF-beta1 in the cancerization of oral lichen planus. Head Neck. 2008;30(9):1237–45. Scholar
  93. 93.
    Cao Q, Jiang Y, Shi J, Xu C, Liu X, Yang T, et al. Artemisinin inhibits the proliferation, migration, and inflammatory reaction induced by tumor necrosis factor-a in vascular smooth muscle cells through nuclear factor kappa B pathway. J Surg Res. 2015;194(2):667–78.PubMedCrossRefGoogle Scholar
  94. 94.
    Li Y, Wang S, Wang Y, Zhou C, Chen G, Shen W, et al. Inhibitory effect of the antimalarial agent artesunate on collagen-induced arthritis in rats through nuclear factor kappa B and mitogen-activated protein kinase signaling pathway. Transl Res. 2013;161(2):89–98. Scholar
  95. 95.
    Que Z, Wang P, Hu Y, Xue Y, Liu X, Qu C, et al. Dihydroartemisin inhibits glioma invasiveness via a ROS to P53 to β-catenin signaling. Pharmacol Res. 2017;119:72–88.PubMedCrossRefGoogle Scholar
  96. 96.
    Xu Y, Liu W, Fang B, Gao S, Yan J. Artesunate ameliorates hepatic fibrosis induced by bovine serum albumin in rats through regulating matrix metalloproteinases. Eur J Pharmacol. 2014;744:1–9. Scholar
  97. 97.
    Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010;40(7):1830–5. Scholar
  98. 98.
    Zhang D, Wang J, Li Z, Zhou M, Chen Q, Zeng X, et al. The activation of NF-κB in infiltrated mononuclear cells negatively correlates with Treg cell frequency in oral lichen planus. Inflammation. 2015;38(4):1683–9. Scholar
  99. 99.
    Marshall A, Celentano A, Cirillo N, McCullough M, Porter S. Tissue-specific regulation of CXCL9/10/11 chemokines in keratinocytes: Implications for oral inflammatory disease. PLoS One. 2017;12(3):e0172821. Scholar
  100. 100.
    Pekiner F, Demirel G, Borahan M, Ozbayrak S. Evaluation of cytotoxic T-cell activation, chemokine receptors, and adhesion molecules in blood and serum in patients with oral lichen planus. J Oral Pathol Med. 2012;41(6):484–9. Scholar
  101. 101.
    Hu JY, Zhang J, Cui JL, Liang XY, Lu R, Du GF, et al. Increasing CCL5/CCR5 on CD4 + T cells in peripheral blood of oral lichen planus. Cytokine. 2013;62(1):141–5. Scholar
  102. 102.
    Chaiyarit P, Ma N, Hiraku Y, Pinlaor S, Yongvanit P, Jintakanon D, et al. Nitrative and oxidative DNA damage in oral lichen planus in relation to human oral carcinogenesis. Cancer Sci. 2005;96(9):553–9. Scholar
  103. 103.
    Ergun S, Troşala ŞC, Warnakulasuriya S, Özel S, Önal AE, Ofluoğlu D, et al. Evaluation of oxidative stress and antioxidant profile in patients with oral lichen planus. J Oral Pathol Med. 2011;40(4):286–93. doi.PubMedCrossRefGoogle Scholar
  104. 104.
    Lysitsa S, Samson J, Gerber-Wicht C, Lang U, Lombardi T. COX-2 expression in oral lichen planus. Dermatology. 2008;217(2):150–5. Scholar
  105. 105.
    Tvarijonaviciute A, Aznar-Cayuela C, Rubio CP, Ceron JJ, Lopez-Jornet P. Evaluation of salivary oxidate stress biomarkers, nitric oxide and C-reactive protein in patients with oral lichen planus and burning mouth syndrome. J Oral Pathol Med. 2017;46(5):387–92. Scholar
  106. 106.
    Mastrangelo F, Grilli A, Tettamanti L, Gatto R, Marzo G, Vinci R, et al. Nitric oxide synthase isoenzyme expression in human oral lichen planus. J Biol Regul Homeost Agents. 2013;27(4):1069–75.PubMedGoogle Scholar
  107. 107.
    Panjwani S, Bagewadi A, Keluskar V, Malik R, Rai S, Misra D. Estimation and comparison of levels of salivary nitric oxide in patients with oral lichen planus and controls. Int J Prev Med. 2013;4(6):710–4.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Mehdipour M, Taghavi Zenouz A, Bahramian A, Gholizadeh N, Boorghani M. Evaluation of serum nitric oxide level in patients with oral lichen planus. J Dent. 2014;15(2):48–51.Google Scholar
  109. 109.
    Zhu XX, Yang L, Li YJ, Zhang D, Chen Y, Kostecka P, et al. Effects of sesquiterpene, flavonoid and coumarin types of compounds from Artemisia annua L. on production of mediators of angiogenesis. Pharmacol Rep. 2013;65(2):410–20.PubMedCrossRefGoogle Scholar
  110. 110.
    Guruprasad B, Chaudhary P, Choedon T, Kumar VL. Artesunate ameliorates functional limitations in Freund’s complete adjuvant-induced monoarthritis in Rat by maintaining oxidative homeostasis and inhibiting COX-2 expression. Inflammation. 2015;38(3):1028–35. Scholar
  111. 111.
    Verma S, Kumar VL. Attenuation of gastric mucosal damage by artesunate in rat: Modulation of oxidative stress and NFkB mediated signaling. Chem Biol Interact. 2016;257:46–53.PubMedCrossRefGoogle Scholar
  112. 112.
    Pigatto PD, Spadari F, Bombeccari GP, Guzzi G. Increased levels of COX-2 and oral lichen planus. J Eur Acad Dermatol Venereol. 2013;27(3):395. Scholar
  113. 113.
    Li TJ, Cui J. COX-2, MMP-7 expression in oral lichen planus and oral squamous cell carcinoma. Asian Pac J Trop Med. 2013;6(8):640–3. Scholar
  114. 114.
    Chankong T, Chotjumlong P, Sastraruji T, Pongsiriwet S, Iamaroon A, Krisanaprakornkit S. Increased cyclooxygenase 2 expression in association with oral lichen planus severity. J Dental Sci. 2016;11(3):238–44. Scholar
  115. 115.
    Danielsson K, Ebrahimi M, Wahlin YB, Nylander K, Boldrup L. Increased levels of COX-2 in oral lichen planus supports an autoimmune cause of the disease. J Eur Acad Dermatol Venereol. 2012;26(11):1415–9. Scholar
  116. 116.
    Abdel Hay RM, Fawzy MM, Metwally D, Kadry D, Ezzat M, Rashwan W, et al. DNA polymorphisms and tissue cyclooxygenase-2 expression in oral lichen planus: a case-control study. J Eur Acad Dermatol Venereol. 2012;26(9):1122–6. Scholar
  117. 117.
    Ho W, Peh H, Chan T, Wong W. Artemisinins: pharmacological actions beyond anti-malarial. Pharmacol Ther. 2014;142(1):126–39. Scholar
  118. 118.
    Galal AM, Ross SA, Jacob M, ElSohly MA. Antifungal activity of artemisinin derivatives. J Nat Prod. 2005;68(8):1274–6. Scholar
  119. 119.
    De Cremer K, Lanckacker E, Cools TL, Bax M, De Brucker K, Cos P, et al. Artemisinins, new miconazole potentiators resulting in increased activity against Candida albicans biofilms. Antimicrob Agents chemother. 2015;59(1):421–6. Scholar
  120. 120.
    Buragohain P, Surineni N, Barua NC, Bhuyan PD, Boruah P, Borah JC, et al. Synthesis of a novel series of fluoroarene derivatives of artemisinin as potent antifungal and anticancer agent. Bioorg Med Chem Lett. 2015;25(16):3338–41. Scholar
  121. 121.
    WHO Guidelines Approved by the Guidelines Review Committee. Guidelines for the treatment of Malaria. 3rd ed. Geneva: World Health Organization; 2015.Google Scholar
  122. 122.
    Efferth T, Kaina B. Toxicity of the antimalarial artemisinin and its dervatives. Crit Rev Toxicol. 2010;40(5):405–21. Scholar
  123. 123.
    Burger RJ, Visser BJ, Grobusch MP, van Vugt M. The influence of pregnancy on the pharmacokinetic properties of artemisinin combination therapy (ACT): a systematic review. Malaria J. 2016;15:99. Scholar
  124. 124.
    McGready R, Cho T, Villegas L, Brockman A, van Vugt M, et al. Randomized comparison of quinine-clindamycin versus artesunate in the treatment of falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg. 2001;95(6):651–6. Scholar
  125. 125.
    McGready R, Tan SO, Ashley EA, Pimanpanarak M, Viladpai-Nguen J, Phaiphun L, et al. A randomised controlled trial of artemether-lumefantrine versus artesunate for uncomplicated plasmodium falciparum treatment in pregnancy. PLoS Med. 2008;5(12):e253. Scholar
  126. 126.
    Taylor WR, White NJ. Antimalarial drug toxicity: a review. Drug Saf. 2004;27(1):25–61. Scholar
  127. 127.
    Serra P, Santamaria P. Nanoparticle-based autoimmune disease therapy. Clin Immunol. 2015;160(1):3–13. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of StomatologyWuhan UniversityWuhanPeople’s Republic of China
  2. 2.Department of Oral Medicine, School and Hospital of StomatologyWuhan UniversityWuhanPeople’s Republic of China

Personalised recommendations