Effect of tagitinin C isolated from kembang bulan [Tithonia diversifolia (Hemsley) A. Gray] leaves on VEGF and TNF-α expressions ofkeloid fibroblast


Arif Yusuf Wicaksana(1*), Dwi Aris Nugrahaningsih(2), Mae Sri Hartati Wahyuningsih(3)

(1) Faculty of Health Sciences, Universitas ‘Aisyiyah, Yogyakarta,
(2) Department of Pharmacology and Therapy, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta
(3) Department of Pharmacology and Therapy, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta
(*) Corresponding Author


Tagitinin C, an active constituent of Tithonia diversifolia (Hemsley) A. Gray, has  been proven can inhibit the collagen deposition of keloid fibroblasts in vitro.  However, its mechanism of action has not been widely studied. One possible mechanism involves growth factors and cytokines. Vascular endothelial growth  factor (VEGF) and tumor necrosis factor alpha (TNF-α) play an important role  in the collagen deposition. The study aimed to evaluate the effect of tagitinin  C on VEGF and TNF-α expression in keloid fibroblasts culture. An experimental  laboratory study using fibroblast cell lines at passages III and IV was performed.  Treatments were divided into two groups i.e. the treatment groups after incubation with tagitinin C at various concentration of 1, 0.5, 0.25, and 0.125μg/ mL for 72 h, and the control group using culture media without tagitinin C.  Following after incubation, the VEGF and TNF-α levels of keloid fibroblast culture supernatant were measured by ELISA. Kruskal-Wallis test continued  using Mann-Whitney test or one way Anova continued by independent t test  were applied to evaluate the differences between groups. A p value of less  than 0.05 was considered statistically significant. The VEGF levels significantly  decreases in concentration-dependent manner after treatment of the tagitinin C at various concentrations (p<0.05). However, no significantly difference in  TNF-α levels was observed (p> 0.05). In conclusion, tagitinin C decreases the  VEGF expression of keloid fibroblasts. However, it has no effect on the TNF-α  expression.


keloid fibroblast; cell proliferation; tagitinin C; VEGF; TNF-α;

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  1. Seo BF, Lee JY,Jung SN. Models of abnormal scarring. BioMed Res Int 2013; Article ID 423147, 8 pages. https://doi.org/10.1155/2013/423147
  2. Shih B, Garside E, McGrouthe DA, Bayat A. Molecular dissection of abnormal wound healing processes resulting in keloid disease. Wound Rep Reg 2010; 18:139-53. https://doi.org/10.1111/j.1524-475X.2009.00553.x
  3. Lohela M, Bry M, Tammela T, Alitalo K. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol 2009; 21:154-65. https://doi.org/10.1016/j.ceb.2008.12.012
  4. Wu WS, Wang FS, Yang KD, Haung CC, Dacks JM, Kuo YR. Dexamethasone induction of keloid regression through effective suppression of VEGF expression and keloid fibroblast proliferation. J Invest Dermatol 2006; 126:1264-71. https://doi.org/ 10.1038/sj.jid.5700274
  5. Duque GA, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol 2014; 5:491. https://doi.org/10.3389/fimmu.2014.00491
  6. Shah S, Amini-Nik S. The role of phytochemicals in the inflammatoryphase of wound healing. Int J Mol Sci 2017; 18:1068. https://doi.org/10.3390/ijms18051068
  7. Block L, Gosain A, King TW. Emerging therapies for scar prevention. Adv Wound Care (New Rochelle) 2015; 4(10):607–14. https://doi.org/10.1089/wound.2015.0646
  8. Lu MR, Huang HL, Chiou WF, Huang RL. Induction of apoptosis by Tithoniadiversifolia in human hepatoma cells. Pharmacogn Mag 2017; 13(52):702–6. https://doi.org/10.4103/0973-1296.218113
  9. Mardihusodo HR, Wahyuningsih MSH, Astuti I. The effect of active compound isolated from the leaves of kembangbulan [Tithoniadiversifolia (Hemsley) A. Gray] on cell cycle and angiogenesis of WiDr cell line. J Med Sci 2013; 45(3):101-11. https://doi.org/10.19106/JMedScie004503201301
  10. Wahyuningsih MSH, Widodo YW, Hidayat R, Sadid A. Antifibrotic effect of standardized ethanol extract of Tithoniadiversifolia (Hemsley) A. Gray on keloid fibroblasts. Int J Pharm Pharm Sci 2015; 7(4):642-7.
  11. Wahyuningsih MSH, Nugrahaningsih DAA, Budiyanto A. Ethanolic extract of Tithonia diversifolia (Hemsley) A. Gray inhibits migration activity and decrease the TGF-β1,VEGF expression on keloid fibroblasts. Asian J Pharm Clin Res 2019; 12(1):342-5. https://doi.org/10.22159/ajpcr.2019.v12i1.29850
  12. Ranti I, Wahyuningsih MSH, Wirohadidjojo YW. The antifibrotic effect of isolate tagitinin C from Tithonia diversifolia (Hemsley) A. Gray on keloid fibroblast cell. Pan Afr Med J 2018; 30:264. https://doi.org/10.11604/pamj.2018.30.264.9994
  13. Santi E, Wahyuningsih MSH, Budiyanto A. Effect of tagitinin C isolated from Tithonia diversifolia (Hemsley) A. Gray on migration activity and TGF-β1 levels on keloid fibroblast. JMed Sci 2019; 51(3):188-94. https://doi.org/10.19106/JMedSci005103201901
  14. Wahyuningsih MSH, Wijayanti MA, Budiyanto A, Hanafi M. Isolation and identification of potential cytotoxic compound from kembang bulan [Tithoniadiversifolia (Hemsley) A. Gray] leaves. Int J Pharm Pharm Sci 2015; 7(6):298-301.
  15. Johnson KE, Wilgus TA. Vascular endothelial growth factor and angiogenesis in the regulation of cutaneous wound repair. Adv Wound Care (New Rochelle) 2014; 3(10):647-61. https://doi.org/10.1089/wound.2013.0517
  16. Brem H, Kodra A, Golinko MS, Entero H, Stojadinovic O, Wang VM, et al. Mechanism of sustained release of vascular endothelial growth factor in accelerating experimental diabetic healing. J Invest Dermatol 2009; 129(9):2275-87. https://doi.org/ 10.1038/jid.2009.26
  17. Limandjaja GC, van den Broek LJ, Waaijman T, van Veen HA, Everts V, Monstrey S, et al. Increased epidermal thickness andabnormal epidermal differentiation in keloid scars. Br J Dermatol 2017; 176(1):116-26. https://doi.org/10.1016/j.burns.2017.08.017
  18. Zhang Z, Nie F, Kang C, Chen B, Qin Z, Ma J, et al. Increased periostin expression affects the proliferation, collagen synthesis, migration and invasion of keloid fibroblasts under hypoxic conditions. Int J Mol Med 2014; 34(1):253-61. https://doi.org/10.3892/ijmm.2014.1760
  19. Zhang Z, Cao G, Sha L, Wang D, Liu M.The efficacy of sodium aescinate on cutaneous wound healing in diabetic rats. Inflammation 2015; 38(5):1942–48. https://doi.org/10.1007/s10753-015-0174-5
  20. Ahluwalia A, Tarnawski AS. Critical role of hypoxia sensor - HIF-1alpha in VEGF gene activation. Implications for angiogenesis and tissue injury healing. Curr Med Chem 2012; 19(1):90-7. https://doi.org/0.2174/ 092986712803413944
  21. Ong CT, Khoo YT, Tan EK, Mukhopadhyay A, Do DV, Han HC, et al. Epithelial-mesenchymal interactions in keloid pathogenesis modulate vascular endothelial growth factor expression and secretion. J Pathol 2007; 211(1):95-108. https://doi.org/ 10.1002/path.2081
  22. Guo G, Feng H, Xin Y. The effect of pentoxifylline on IL-6 and PDGF expression in human keloid fibroblasts. Disc Clin Cases 2015; 2(3):7-10. https://doi.org/10.14725/dcc.v2n3p7

DOI: https://doi.org/10.19106/JMedSci005204202001

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Journal of the Medical Sciences (Berkala Ilmu Kedokteran) by  Universitas Gadjah Mada is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Based on a work at http://jurnal.ugm.ac.id/bik/.