Parasites, Hosts and Diseases

The Korea Society for Parasitology and Tropical Medicine (대한기생충학·열대의학회)
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Dipenyleneiodonium Induces Growth Inhibition of Toxoplasma gondii through ROS Induction in ARPE-19 Cells

  • Sun, Pu Reum (Department of Medical Science & Infection Biology, Chungnam National University, School of Medicine) ;
  • Gao, Fei Fei (Department of Medical Science & Infection Biology, Chungnam National University, School of Medicine) ;
  • Choi, Hei Gwon (Department of Medical Science & Infection Biology, Chungnam National University, School of Medicine) ;
  • Zhou, Wei (Department of Medical Science & Infection Biology, Chungnam National University, School of Medicine) ;
  • Yuk, Jae-Min (Department of Medical Science & Infection Biology, Chungnam National University, School of Medicine) ;
  • Kwon, Jaeyul (Department of Medical Science & Medical Education, Chungnam National University, School of Medicine) ;
  • Lee, Young-Ha (Department of Medical Science & Infection Biology, Chungnam National University, School of Medicine) ;
  • Cha, Guang-Ho (Department of Medical Science & Infection Biology, Chungnam National University, School of Medicine)
  • Received : 2018.10.30
  • Accepted : 2019.03.14
  • Published : 2019.04.30
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Abstract

Based on the reactive oxygen species (ROS) regulatory properties of diphenyleneiodonium (DPI), we investigated the effects of DPI on host-infected T. gondii proliferation and determined specific concentration that inhibit the intracellular parasite growth but without severe toxic effect on human retinal pigment epithelial (ARPE-19) cells. As a result, it is observed that host superoxide, mitochondria superoxide and $H_2O_2$ levels can be increased by DPI, significantly, followed by suppression of T. gondii infection and proliferation. The involvement of ROS in anti-parasitic effect of DPI was confirmed by finding that DPI effect on T. gondii can be reversed by ROS scavengers, N-acetyl-L-cysteine and ascorbic acid. These results suggest that, in ARPE-19 cell, DPI can enhance host ROS generation to prevent T. gondii growth. Our study showed DPI is capable of suppressing T. gondii growth in host cells while minimizing the un-favorite side-effect to host cell. These results imply that DPI as a promising candidate material for novel drug development that can ameliorate toxoplasmosis based on ROS regulation.

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References

  1. Tenter AM, Heckeroth AR, Weiss LM. Toxoplasma gondii: from animals to humans. Int J Parasitol 2000; 30: 1217-1258. https://doi.org/10.1016/S0020-7519(00)00124-7
  2. Park YH, Nam HW. Clinical features and treatment of ocular toxoplasmosis. Korean J Parasitol 2013; 51: 393-399. https://doi.org/10.3347/kjp.2013.51.4.393
  3. Cai J, Nelson KC, Wu M, Sternberg P Jr, Jones DP. Oxidative damage and protection of the RPE. Prog Retin Eye Res 2000; 19: 205-221. https://doi.org/10.1016/S1350-9462(99)00009-9
  4. Espinosa A, Henriquez-Olguin C, Jaimovich E. Reactive oxygen species and calcium signals in skeletal muscle: a crosstalk involved in both normal signaling and disease. Cell Calcium 2016; 60: 172-179. https://doi.org/10.1016/j.ceca.2016.02.010
  5. Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O. Oxidative stress and antioxidant defense. World Allergy Organ J 2012; 5: 9-19. https://doi.org/10.1097/WOX.0b013e3182439613
  6. Woods JR Jr, Plessinger MA, Fantel A. An introduction to reactive oxygen species and their possible roles in substance abuse. Obstet Gynecol Clin North Am 1998; 25: 219-236. https://doi.org/10.1016/S0889-8545(05)70366-1
  7. Massart C, Giusti N, Beauwens R, Dumont JE, Miot F, Sande JV. Diphenyleneiodonium, an inhibitor of NOXes and DUOXes, is also an iodide-specific transporter. FEBS Open Bio 2013; 4: 55-59. https://doi.org/10.1016/j.fob.2013.11.007
  8. Szilagyi JT, Mishin V, Heck DE, Jan YH, Aleksunes LM, Richardson JR, Heindel ND, Laskin DL, Laskin JD. Selective targeting of heme protein in cytochrome P450 and nitric oxide synthase by diphenyleneiodonium. Toxicol Sci 2016; 151: 150-159. https://doi.org/10.1093/toxsci/kfw031
  9. Sharma M, Sharma KB, Chauhan S, Bhattacharyya S, Vrati S, Kalia M. Diphenyleneiodonium enhances oxidative stress and inhibits Japanese encephalitis virus induced autophagy and ER stress pathways. Biochem Biophys Res Commun 2018; 502: 232-237. https://doi.org/10.1016/j.bbrc.2018.05.149
  10. Zhou W, Quan JH, Gao FF, Ismail HAHA, Lee YH, Cha GH. Modulated gene expression of Toxoplasma gondii infected retinal pigment epithelial cell line (ARPE-19) via PI3K/Akt or mTOR signal pathway. Korean J Parasitol 2018; 56: 135-145. https://doi.org/10.3347/kjp.2018.56.2.135
  11. Kucera J, Bino L, Stefkova K, Jaros J, Vasicek O, Vecera J, Kubala L, Pachernik J. Apocynin and diphenyleneiodonium induce oxidative stress and modulate PI3K/Akt and MAPK/Erk activity in mouse embryonic stem cells. Oxid Med Cell Longev 2016; 2016: 7409196. https://doi.org/10.1155/2016/7409196
  12. Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, Melendez JA, Robinson JP. DPI induces mitochondrial superoxide-mediated apoptosis. Free Radic Biol Med 2003; 34: 465-477. https://doi.org/10.1016/S0891-5849(02)01325-4
  13. Clough B, Wright JD, Pereira PM, Hirst EM, Johnston AC, Henriques R, Frickel EM. K63-linked ubiquitination targets Toxoplasma gondii for endo-lysosomal destruction in $IFN{\gamma}$-stimulated human cells. PLoS Pathog 2016; 12: e1006027. https://doi.org/10.1371/journal.ppat.1006027
  14. Li Y, Trush MA. Diphenyleneiodonium, an NAD(P)H oxidase inhibitor, also potently inhibits mitochondrial reactive oxygen species production. Biochem Biophys Res Commun 1998; 253: 295-299. https://doi.org/10.1006/bbrc.1998.9729
  15. Park SE, Song JD, Kim KM, Park YM, Kim ND, Yoo YH, Park YC. Diphenyleneiodonium induces ROS-independent p53 expression and apoptosis in human RPE cells. FEBS Lett 2007; 581: 180-186. https://doi.org/10.1016/j.febslet.2006.12.006
  16. Riganti C, Gazzano E, Polimeni M, Costamagna C, Bosia A, Ghigo D. Diphenyleneiodonium inhibits the cell redox metabolism and induces oxidative stress. J Biol Chem 2004; 279: 47726-47731. https://doi.org/10.1074/jbc.M406314200
  17. Stowe DF, Camara AK. Mitochondrial reactive oxygen species production in excitable cells: modulators of mitochondrial and cell function. Antioxid Redox Signal 2009; 11: 1373-1414. https://doi.org/10.1089/ars.2008.2331

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