Cellular and Molecular Life Sciences

, Volume 75, Issue 3, pp 563–588 | Cite as

Ammonium trichloro [1,2-ethanediolato-O,O′]-tellurate cures experimental visceral leishmaniasis by redox modulation of Leishmania donovani trypanothione reductase and inhibiting host integrin linked PI3K/Akt pathway

  • Preeti Vishwakarma
  • Naveen Parmar
  • Pragya Chandrakar
  • Tanuj Sharma
  • Manoj Kathuria
  • Pramod K. Agnihotri
  • Mohammad Imran Siddiqi
  • Kalyan Mitra
  • Susanta Kar
Original Article


In an endeavor to search for affordable and safer therapeutics against debilitating visceral leishmaniasis, we examined antileishmanial potential of ammonium trichloro [1,2-ethanediolato-O,O′]-tellurate (AS101); a tellurium based non toxic immunomodulator. AS101 showed significant in vitro efficacy against both Leishmania donovani promastigotes and amastigotes at sub-micromolar concentrations. AS101 could also completely eliminate organ parasite load from L. donovani infected Balb/c mice along with significant efficacy against infected hamsters (˃93% inhibition). Analyzing mechanistic details revealed that the double edged AS101 could directly induce apoptosis in promastigotes along with indirectly activating host by reversing T-cell anergy to protective Th1 mode, increased ROS generation and anti-leishmanial IgG production. AS101 could inhibit IL-10/STAT3 pathway in L. donovani infected macrophages via blocking α4β7 integrin dependent PI3K/Akt signaling and activate host MAPKs and NF-κB for Th1 response. In silico docking and biochemical assays revealed AS101’s affinity to form thiol bond with cysteine residues of trypanothione reductase in Leishmania promastigotes leading to its inactivation and inducing ROS-mediated apoptosis of the parasite via increased Ca2+ level, loss of ATP and mitochondrial membrane potential along with metacaspase activation. Our findings provide the first evidence for the mechanism of action of AS101 with excellent safety profile and suggest its promising therapeutic potential against experimental visceral leishmaniasis.


AS101 Visceral leishmaniasis Immunomodulator Reactive oxygen species Integrin Redox modulation Apoptosis 



Alpha-4 Beta-7 integrin


Ammonium trichloro [1,2-ethanediolato-O,O′]-tellurate


Carbonyl cyanide 3-chlorophenylhydrazone


5,5-Dithio-bis-(2-nitrobenzoic acid)


Electrophoretic mobility shift assay


2′,7′-dichlorodihydrofluorescein diacetate


50% Inhibitory concentration


Interferon gamma


Interlukin 10


Intra peritoneal


5,5′,6,6′-tetra-chloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide

L. donovani

Leishmania donovani


Leishman donovan unit


Mitochondrial membrane potential


3-(4,5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide


Propidium iodide


Pentavalent antimonials


Soluble leishmania antigen


Trypanothione reductase


Tellurium with 4 oxidation state


Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling




Trypanothione disulphide


Tumor necrosis factor alpha


Transforming growth factor beta


Visceral leishmaniasis


Aspartate aminotransferase


Alanine aminotransferase



The authors thank Director, CDRI, Lucknow, for providing the research facilities and encouragement. Authors acknowledge sophisticated analytical instrument facility of CDRI for helping with flow cytometry. Authors also thank Technical Officers, Mr. Anurag Kumar Srivastava and Dr. Kavita Singh, from CDRI for helping in performing liver enzyme assays and confocal microscopy experiments. This work was supported by the Department of Science and Technology (Grant no. SB/FT/LS-310/2012), Council of Scientific and Industrial Research (CSIR NWP BSC0114)—Government of India. P. V., P. C., T. S. and M. K. were supported by the fellowship from Council of Scientific and Industrial Research (CSIR). N. P. was supported by the fellowship from University Grant Commission (UGC) of India. This manuscript has CDRI communication no. 9544.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Monge-Maillo B, Norman FF, Cruz I et al (2014) Visceral leishmaniasis and HIV coinfection in the Mediterranean region. PLoS Negl Trop Dis 8:e3021. doi: 10.1371/journal.pntd.0003021 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Das VNR, Ranjan A, Bimal S et al (2005) Magnitude of unresponsiveness to sodium stibogluconate in the treatment of visceral leishmaniasis in Bihar. Natl Med J India 18:131–133PubMedGoogle Scholar
  3. 3.
    Jain K, Jain NK (2015) Vaccines for visceral leishmaniasis: a review. J Immunol Methods 422:1–12. doi: 10.1016/j.jim.2015.03.017 CrossRefPubMedGoogle Scholar
  4. 4.
    Ivens AC, Peacock CS, Worthey EA et al (2005) The genome of the kinetoplastid parasite, Leishmania major. Science 309:436–442. doi: 10.1126/science.1112680 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hotez PJ (2011) The neglected tropical diseases and the neglected infections of poverty: overview of their common features, global disease burden and distribution, new control tools, and prospects for disease elimination. National Academies Press (US)Google Scholar
  6. 6.
    Andrews KT, Fisher G, Skinner-Adams TS (2014) Drug repurposing and human parasitic protozoan diseases. Int J Parasitol Drugs Drug Resist 4:95–111. doi: 10.1016/j.ijpddr.2014.02.002 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Croft SL, Coombs GH (2003) Leishmaniasis–current chemotherapy and recent advances in the search for novel drugs. Trends Parasitol 19:502–508CrossRefPubMedGoogle Scholar
  8. 8.
    Liew FY, Millott S, Parkinson C et al (1990) Macrophage killing of Leishmania parasite in vivo is mediated by nitric oxide from l-arginine. J Immunol 144:4794–4797PubMedGoogle Scholar
  9. 9.
    Ruhland A, Leal N, Kima PE (2007) Leishmania promastigotes activate PI3K/Akt signalling to confer host cell resistance to apoptosis. Cell Microbiol 9:84–96. doi: 10.1111/j.1462-5822.2006.00769.x CrossRefPubMedGoogle Scholar
  10. 10.
    Reiner SL, Locksley RM (1995) The regulation of immunity to Leishmania major. Annu Rev Immunol 13:151–177. doi: 10.1146/annurev.iy.13.040195.001055 CrossRefPubMedGoogle Scholar
  11. 11.
    Srivastav S, Basu Ball W, Gupta P et al (2013) Leishmania donovani prevents oxidative burst-mediated apoptosis of host macrophages through selective induction of suppressors of cytokine signaling (SOCS) proteins. J Biol Chem 289:1092–1105. doi: 10.1074/jbc.M113.496323 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Heussler VT, Küenzi P, Rottenberg S (2001) Inhibition of apoptosis by intracellular protozoan parasites. Int J Parasitol 31:1166–1176CrossRefPubMedGoogle Scholar
  13. 13.
    Das M, Saudagar P, Sundar S, Dubey VK (2013) Miltefosine-unresponsive Leishmania donovani has a greater ability than miltefosine-responsive L. donovani to resist reactive oxygen species. FEBS J 280:4807–4815. doi: 10.1111/febs.12449 CrossRefPubMedGoogle Scholar
  14. 14.
    Cunha RLOR, Gouvea IE, Juliano L (2009) A glimpse on biological activities of tellurium compounds. Anais da Academia Brasileira 81:393–407CrossRefGoogle Scholar
  15. 15.
    Sredni B, Weil M, Khomenok G et al (2004) Ammonium trichloro (dioxoethylene-O,O′) tellurate (AS101) sensitizes tumors to chemotherapy by inhibiting the tumor interleukin 10 autocrine loop. Cancer Res 64:1843–1852. doi: 10.1158/0008-5472.CAN-03-3179 CrossRefPubMedGoogle Scholar
  16. 16.
    Sredni B, Geffen-Aricha R, Duan W et al (2007) Multifunctional tellurium molecule protects and restores dopaminergic neurons in Parkinson’s disease models. FASEB J 21:1870–1883. doi: 10.1096/fj.06-7500com CrossRefPubMedGoogle Scholar
  17. 17.
    Okun E, Arumugam TV, Tang S-C et al (2007) The organotellurium compound ammonium trichloro (dioxoethylene-O,O′) tellurate enhances neuronal survival and improves functional outcome in an ischemic stroke model in mice. J Neurochem 102:1232–1241. doi: 10.1111/j.1471-4159.2007.04615.x CrossRefPubMedGoogle Scholar
  18. 18.
    Yosef S, Brodsky M, Sredni B et al (2007) Octa-O-bis-(R,R)-tartarate ditellurane (SAS)—a novel bioactive organotellurium(IV) compound: synthesis, characterization, and protease inhibitory activity. ChemMedChem 2:1601–1606. doi: 10.1002/cmdc.200700155 CrossRefPubMedGoogle Scholar
  19. 19.
    Qasimi P, Ming-Lum A, Ghanipour A et al (2006) Divergent mechanisms utilized by SOCS3 to mediate interleukin-10 inhibition of tumor necrosis factor alpha and nitric oxide production by macrophages. J Biol Chem 281:6316–6324. doi: 10.1074/jbc.M508608200 CrossRefPubMedGoogle Scholar
  20. 20.
    Biswas A, Bhattacharya A, Kar S, Das PK (2011) Expression of IL-10-triggered STAT3-dependent IL-4Rα is required for induction of arginase 1 in visceral leishmaniasis. Eur J Immunol 41:992–1003. doi: 10.1002/eji.201040940 CrossRefPubMedGoogle Scholar
  21. 21.
    Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63CrossRefPubMedGoogle Scholar
  22. 22.
    Stauber LA (1958) Host Resistance to the Khartoum Strain of Leishmania donovani. vol 45. Rice Institute Pamphlet-Rice University Studies, TX, USA, pp 80–96Google Scholar
  23. 23.
    Mukhopadhyay S, Sen P, Bhattacharyya S et al (1999) Immunoprophylaxis and immunotherapy against experimental visceral leishmaniasis. Vaccine 17:291–300. doi: 10.1016/S0264-410X(98)90017-2 CrossRefPubMedGoogle Scholar
  24. 24.
    Shivahare R, Vishwakarma P, Parmar N et al (2014) Combination of liposomal CpG oligodeoxynucleotide 2006 and miltefosine induces strong cell-mediated immunity during experimental visceral leishmaniasis. PLoS One 9:e94596. doi: 10.1371/journal.pone.0094596 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Chowdhury S, Mukherjee T, Mukhopadhyay R et al (2012) The lignan niranthin poisons Leishmania donovani topoisomerase IB and favours a Th1 immune response in mice. EMBO Mol Med 4:1126–1143. doi: 10.1002/emmm.201201316 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Coumbarides GS, Alvar J, Seifert K et al (2015) Chemical and bioassay techniques to authenticate quality of the anti-leishmanial drug miltefosine. Am J Trop Med Hyg 92:31–38. doi: 10.4269/ajtmh.14-0586 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kar S, Sharma G, Das PK (2011) Fucoidan cures infection with both antimony-susceptible and -resistant strains of Leishmania donovani through Th1 response and macrophage-derived oxidants. J Antimicrob Chemother 66:618–625. doi: 10.1093/jac/dkq502 CrossRefPubMedGoogle Scholar
  28. 28.
    Cunha-ju F, Pinheiro RO, Ribeiro GA et al (2013) LQB-118, an orally active pterocarpanquinone, induces selective oxidative stress and apoptosis in Leishmania amazonensis. J Antimicrob Chemother 68:789–799. doi: 10.1093/jac/dks498 CrossRefGoogle Scholar
  29. 29.
    Park SY, Kim JH, Lee YJ et al (2013) Surfactin suppresses TPA-induced breast cancer cell invasion through the inhibition of MMP-9 expression. Int J Oncol 42:287–296. doi: 10.3892/ijo.2012.1695 CrossRefPubMedGoogle Scholar
  30. 30.
    Kar S, Palit S, Basu W (2012) Carnosic acid modulates Akt/IKK/NF-KB signaling by PP2A and induces intrinsic and extrinsic pathway mediated apoptosis in human prostate carcinoma PC-3 cells. Apoptosis 17:735–747. doi: 10.1007/s10495-012-0715-4 CrossRefPubMedGoogle Scholar
  31. 31.
    Mayer LP, Dyer CA, Eastgard RL et al (2005) Atherosclerotic lesion development in a novel ovary-intact mouse model of perimenopause. Arterioscler Thromb Vasc Biol 25:1910–1916. doi: 10.1161/01.ATV.0000175767.46520.6a CrossRefPubMedGoogle Scholar
  32. 32.
    Pimentel IAS, de Siqueira Paladi C, Katz S et al (2012) In vitro and in vivo activity of an organic tellurium compound on Leishmania chagasi. PLoS One 7:1–8. doi: 10.1371/journal.pone.0048780 Google Scholar
  33. 33.
    Yamamoto ES, Campos BLS, Jesus JA, Laurenti MD (2015) The effect of ursolic acid on Leishmania (Leishmania) amazonensis is related to programed cell death and presents therapeutic potential in experimental cutaneous leishmaniasis. PLoS One 10:1–19. doi: 10.1371/journal.pone.0144946 Google Scholar
  34. 34.
    Das M, Mukherjee SB, Shaha C (2001) Hydrogen peroxide induces apoptosis-like death in Leishmania donovani promastigotes. J Cell Sci 114:2461–2468PubMedGoogle Scholar
  35. 35.
    Dolai S, Pal S, Yadav RK, Adak S (2011) Endoplasmic reticulum stress-induced apoptosis in leishmania through Ca2+-dependent and caspase-independent mechanism. J Biol Chem 286:13638–13646. doi: 10.1074/jbc.M110.201889 CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Chowdhury S, Mukherjee T, Chowdhury SR et al (2014) Disuccinyl betulin triggers metacaspase-dependent endonuclease G-mediated cell death in unicellular protozoan parasite Leishmania donovani. Antimicrob Agents Chemother 58:2186–2201. doi: 10.1128/AAC.02193-13 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Kathuria M, Bhattacharjee A, Sashidhara KV, Singh P (2014) Induction of mitochondrial dysfunction and oxidative stress in Leishmania donovani by orally active clerodane diterpene. Ant 58:5916–5928. doi: 10.1128/AAC.02459-14 Google Scholar
  38. 38.
    Sundar S, Schallig HDFH, Adams R (2014) Simple colorimetric trypanothione reductase-based assay for high-throughput screening of drugs against Leishmania intracellular amastigotes. Antimicrob Agents Chemother 58:527–535. doi: 10.1128/AAC.00751-13 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Mandal G, Mandal S, Sharma M et al (2015) Species-specific antimonial sensitivity in Leishmania is driven by post-transcriptional regulation of AQP1. PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0003500 Google Scholar
  40. 40.
    Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Crystallogr 26:283–291. doi: 10.1107/S0021889892009944 CrossRefGoogle Scholar
  41. 41.
    Xia W, Springer TA (2014) Metal ion and ligand binding of integrin α5β1. Proc Natl Acad Sci USA 111:17863–17868. doi: 10.1073/pnas.1420645111 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Dong X, Hudson NE, Lu C, Springer TA (2014) Structural determinants of integrin β-subunit specificity for latent TGF-β. Nat Struct Mol Biol 21:1091–1096. doi: 10.1038/nsmb.2905 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Yu Y, Zhu J, Mi L-Z et al (2012) Structural specializations of α(4)β(7), an integrin that mediates rolling adhesion. J Cell Biol 196:131–146. doi: 10.1083/jcb.201110023 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Wu G, Robertson DH, Brooks CL, Vieth M (2003) Detailed analysis of grid-based molecular docking: a case study of CDOCKER-A CHARMm-based MD docking algorithm. J Comput Chem 24:1549–1562. doi: 10.1002/jcc.10306 CrossRefPubMedGoogle Scholar
  45. 45.
    Pettersen EF, Goddard TD, Huang CC et al (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612. doi: 10.1002/jcc.20084 CrossRefPubMedGoogle Scholar
  46. 46.
    Nandan D, Camargo de Oliveira C, Moeenrezakhanlou A et al (2012) Myeloid Cell IL-10 production in response to Leishmania involves inactivation of glycogen synthase kinase-3 downstream of phosphatidylinositol-3 kinase. J Immunol 188:367–378. doi: 10.4049/jimmunol.1100076 CrossRefPubMedGoogle Scholar
  47. 47.
    Feng G, Goodridge HS, Harnett MM et al (1999) Extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases differentially regulate the lipopolysaccharide-mediated induction of inducible nitric oxide synthase and IL-12 in macrophages: leishmania phosphoglycans subvert macr. J Immunol 163:6403–6412PubMedGoogle Scholar
  48. 48.
    Halpert G, Sredni B (2014) The effect of the novel tellurium compound AS101 on autoimmune diseases. Autoimmun Rev 13:1230–1235. doi: 10.1016/j.autrev.2014.08.003 CrossRefPubMedGoogle Scholar
  49. 49.
    Koistinen P, Heino J (2000) Integrins in cancer cell invasion. Landes Bioscience, Austin (TX)Google Scholar
  50. 50.
    Tejle K, Lindroth M, Magnusson KE, Rasmusson B (2008) Wild-type Leishmania donovani promastigotes block maturation, increase integrin expression and inhibit detachment of human monocyte-derived dendritic cells—the influence of phosphoglycans. FEMS Microbiol Lett 279:92–102. doi: 10.1111/j.1574-6968.2007.01013.x CrossRefPubMedGoogle Scholar
  51. 51.
    Szallies A, Kubata BK, Duszenko M (2002) A metacaspase of Trypanosoma brucei causes loss of respiration competence and clonal death in the yeast Saccharomyces cerevisiae. FEBS Lett 517:144–150. doi: 10.1016/S0014-5793(02)02608-X CrossRefPubMedGoogle Scholar
  52. 52.
    Foucher AL, Rachidi N, Gharbi S et al (2013) Apoptotic marker expression in the absence of cell death in staurosporine-treated Leishmania donovani. Antimicrob Agents Chemother 57:1252–1261. doi: 10.1128/AAC.01983-12 CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Kulkarni MM, Mcmaster WR, Kamysz W, Mcgwire BS (2009) Antimicrobial peptide-induced apoptotic death of leishmania results from calcium-dependent, caspase-independent mitochondrial toxicity. J Biol Chem 284:15496–15504. doi: 10.1074/jbc.M809079200 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Mukherjee SB, Das M, Sudhandiran G, Shaha C (2002) Increase in cytosolic Ca2+ levels through the activation of non-selective cation channels induced by oxidative stress causes mitochondrial depolarization leading to apoptosis-like death in Leishmania donovani promastigotes. J Biol Chem 277:24717–24727. doi: 10.1074/jbc.M201961200 CrossRefPubMedGoogle Scholar
  55. 55.
    Reape TJ, McCabe PF (2010) Apoptotic-like regulation of programmed cell death in plants. Apoptosis 15:249–256. doi: 10.1007/s10495-009-0447-2 CrossRefPubMedGoogle Scholar
  56. 56.
    Khare P, Jaiswal AK, Tripathi CDP et al (2014) Efficacy of Leishmania donovani trypanothione reductase, identified as a potent Th1 stimulatory protein, for its immunogenicity and prophylactic potential against experimental visceral leishmaniasis. Parasitol Res 113:851–862. doi: 10.1007/s00436-013-3716-5 CrossRefPubMedGoogle Scholar
  57. 57.
    Frei GM, Lebenthal I, Albeck M et al (2007) Neutral and positively charged thiols synergize the effect of the immunomodulator AS101 as a growth inhibitor of Jurkat cells, by increasing its uptake. Biochem Pharmacol 74:712–722. doi: 10.1016/j.bcp.2007.05.011 CrossRefPubMedGoogle Scholar
  58. 58.
    Ewunetu T (2015) Pro- and anti-inflammatory cytokines in visceral leishmaniasis. J Cell Sci Ther 6:1–8. doi: 10.4172/2157-7013.1000206 Google Scholar
  59. 59.
    Tumang MC, Keogh C, Moldawer LL et al (1994) Role and effect of TNF-alpha in experimental visceral leishmaniasis. J Immunol 153:768–775PubMedGoogle Scholar
  60. 60.
    Stanley AC, Engwerda CR (2007) Balancing immunity and pathology in visceral leishmaniasis. Immunol Cell Biol 85:138–147. doi: 10.1038/sj.icb7100011 CrossRefPubMedGoogle Scholar
  61. 61.
    Padhy BM, Gupta YK (2011) Drug repositioning: re-investigating existing drugs for new therapeutic indications. J Postgrad Med 57:153–160. doi: 10.4103/0022-3859.81870 CrossRefPubMedGoogle Scholar
  62. 62.
    Wyllie S, Patterson S, Stojanovski L et al (2012) The anti-trypanosome drug fexinidazole shows potential for treating visceral leishmaniasis. Sci Transl Med 4:119re1. doi: 10.1126/scitranslmed.3003326 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Daniel-Hoffmann M, Sredni B, Nitzan Y (2012) Bactericidal activity of the organo-tellurium compound AS101 against Enterobacter cloacae. J Antimicrob Chemother 67:2165–2172. doi: 10.1093/jac/dks185 CrossRefPubMedGoogle Scholar
  64. 64.
    Kalich-Philosoph L, Roness H, Carmely A et al (2013) Cyclophosphamide triggers follicle activation and “burnout”; AS101 prevents follicle loss and preserves fertility. Sci Transl Med 5:185ra62. doi: 10.1126/scitranslmed.3005402 CrossRefPubMedGoogle Scholar
  65. 65.
    Ba C, Arrais-silva WW, Luiz R et al (2009) A novel organotellurium compound (RT-01) as a new antileishmanial agent. Korean J Parasitol 47:213–218. doi: 10.3347/kjp.2009.47.3.213 CrossRefGoogle Scholar
  66. 66.
    Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661. doi: 10.1096/fj.07-9574LSF CrossRefPubMedGoogle Scholar
  67. 67.
    Pandey BD, Pandey K, Kaneko O et al (2009) Relapse of visceral leishmaniasis after miltefosine treatment in a Nepalese patient. Am J Trop Med Hyg 80:580–582PubMedGoogle Scholar
  68. 68.
    Sredni B, Tichler T, Shani A et al (1996) Predominance of TH1 response in tumor-bearing mice and cancer patients treated with AS101. J Natl Cancer Inst 88:1276–1284. doi: 10.1093/jnci/88.18.1276 CrossRefPubMedGoogle Scholar
  69. 69.
    Nakahira K, Haspel JA, Rathinam VAK et al (2011) Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12:222–230. doi: 10.1038/ni.1980 CrossRefPubMedGoogle Scholar
  70. 70.
    Bulua AC, Simon A, Maddipati R et al (2011) Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med 208:519–533. doi: 10.1084/jem.20102049 CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Abais JM, Xia M, Zhang Y et al (2015) Redox regulation of NLRP3 inflammasomes: ROS as trigger or effector? Antioxid Redox Signal 22:1111–1129. doi: 10.1089/ars.2014.5994 CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Lu Y, Wahl LM (2005) Oxidative stress augments the production of matrix metalloproteinase-1, cyclooxygenase-2, and prostaglandin E2 through enhancement of NF-κB activity in lipopolysaccharide-activated human primary monocytes. J Immunol 175:5423–5429CrossRefPubMedGoogle Scholar
  73. 73.
    Murray PJ (2006) Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response. Curr Opin Pharmacol 6:379–386. doi: 10.1016/j.coph.2006.01.010 CrossRefPubMedGoogle Scholar
  74. 74.
    Sredni B (2012) Immunomodulating tellurium compounds as anti-cancer agents. Semin Cancer Biol 22:60–69. doi: 10.1016/j.semcancer.2011.12.003 CrossRefPubMedGoogle Scholar
  75. 75.
    Fairlamb AH, Blackburn P, Ulrich P, Chait BT, Cerami A (1985) Trypanothione: a novel bis (glutathionyl) spermidine cofactor for glutathione reductase in trypanosomatids. Science 227:1485–1487CrossRefPubMedGoogle Scholar
  76. 76.
    Gupta R, Kushawaha PK, Samant M et al (2012) Treatment of Leishmania donovani-infected hamsters with miltefosine: analysis of cytokine mRNA expression by real-time PCR, lymphoproliferation, nitrite production and antibody responses. J Antimicrob Chemother 67:440–443. doi: 10.1093/jac/dkr485 CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Preeti Vishwakarma
    • 1
    • 2
  • Naveen Parmar
    • 1
    • 2
  • Pragya Chandrakar
    • 1
    • 2
  • Tanuj Sharma
    • 3
  • Manoj Kathuria
    • 4
  • Pramod K. Agnihotri
    • 5
  • Mohammad Imran Siddiqi
    • 2
    • 3
  • Kalyan Mitra
    • 2
    • 4
  • Susanta Kar
    • 1
    • 2
  1. 1.Division of ParasitologyCSIR-Central Drug Research InstituteLucknowIndia
  2. 2.Academy of Scientific and Innovative ResearchNew DelhiIndia
  3. 3.Molecular and Structural Biology DivisionCSIR-Central Drug Research InstituteLucknowIndia
  4. 4.Electron Microscopy Unit, Sophisticated Analytical Instrument FacilityCSIR-Central Drug Research InstituteLucknowIndia
  5. 5.Division of ToxicologyCSIR-Central Drug Research InstituteLucknowIndia

Personalised recommendations