Advertisement

Archives of Toxicology

, Volume 91, Issue 12, pp 3737–3785 | Cite as

Trichothecenes: immunomodulatory effects, mechanisms, and anti-cancer potential

  • Qinghua Wu
  • Xu Wang
  • Eugenie Nepovimova
  • Anca Miron
  • Qianying Liu
  • Yun Wang
  • Dongxiao Su
  • Hualin Yang
  • Li Li
  • Kamil Kuca
Review Article

Abstract

Paradoxically, trichothecenes have both immunosuppressive and immunostimulatory effects. The underlying mechanisms have not been fully explored. Early studies show that dose, exposure timing, and the time at which immune function is assessed influence whether trichothecenes act in an immunosuppressive or immunostimulatory fashion. Recent studies suggest that the immunomodulatory function of trichothecenes is also actively shaped by competing cell-survival and death-signaling pathways. Autophagy may also promote trichothecene immunosuppression, although the mechanism may be complicated. Moreover, trichothecenes may generate an “immune evasion” milieu that allows pathogens to escape host and vaccine immune defenses. Some trichothecenes, especially macrocyclic trichothecenes, also potently kill cancer cells. T-2 toxin conjugated with anti-cancer monoclonal antibodies significantly suppresses the growth of thymoma EL-4 cells and colon cancer cells. The type B trichothecene diacetoxyscirpenol specifically inhibits the tumor-promoting factor HIF-1 in cancer cells under hypoxic conditions. Trichothecin markedly inhibits the growth of multiple cancer cells with constitutively activated NF-κB. The type D macrocyclic toxin Verrucarin A is also a promising therapeutic candidate for leukemia, breast cancer, prostate cancer, and pancreatic cancer. The anti-cancer activities of trichothecenes have not been comprehensively summarized. Here, we first summarize the data on the immunomodulatory effects of trichothecenes and discuss recent studies that shed light on the underlying cellular and molecular mechanisms. These mechanisms include autophagy and major signaling pathways and their crosstalk. Second, the anti-cancer potential of trichothecenes and the underlying mechanisms will be discussed. We hope that this review will show how trichothecene bioactivities can be exploited to generate therapies against pathogens and cancer.

Keywords

T-2 toxin Deoxynivalenol Immunomodulation Anti-cancer Signaling pathway Autophagy Immune evasion 

Abbreviations

ARNT

Aryl hydrocarbon receptor nuclear translocator

CaSR

Calcium-sensing receptor

CDC

Complement-dependent cytotoxicity

CHOP

Enhancer-binding protein homologous protein

CREB

cAMP-response clement-binding protein

DAS

Diacetoxyscirpenol

DMBA

7,12-Dimethylbenz[a]anthracene

DON

Deoxynivalenol

FB1

Fumonisin B1

FX

Fusarenon X

GFP

Green fluorescence protein

GSH

Glutathione

Hck

Hemopoietic cell kinase

HIF-1

Hypoxia-inducible factor 1

mAb

Monoclonal antibodies

MIP-2

Macrophage inhibitory protein 2

MyD88

Myeloid differentiation factor 88

NIV

Nivalenol

PCD

Programmed cell death

PCV2

Porcine circovirus type 2

PCVAD

Porcine circovirus-associated disease

PI

Post-injection

PKR

RNA-activated protein kinase R

PMNs

Pig polymorphonuclear cells

PP

Peyer’s patch

PRRS

Porcine reproductive and respiratory syndrome

PRRSV

Porcine reproductive and respiratory syndrome virus

PTPC

Permeability transition pore complex

QSAR

Quantitative structure activity relationship

RBC

Sheep red blood cell

RSR

Ribotoxic stress response

SAR

Structure–activity relationships

SMI

Mall molecule inhibitors

SRC

Steroid receptor coactivator

TCN

Trichothecin

TLR

Toll-like Receptors

TPA

12-O-tetradecanoylphorbol-13-acetate

TRAIL

TNF-related apoptosis-inducing ligand

TRPA1

Transient receptor potential ankyrin-1

VA

Verrucarins A

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 31602114 and 31572575), the Yangtze Fund for Youth Teams of Science and Technology Innovation (2016cqt02), the Fundamental Research Funds for the Central Universities (2662016PY115), and the project of long-term development plan UHK.

Compliance with ethical standards

Ethics statement

The manuscript does not contain clinical trials or patient data.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Abbas HK, Johnson BB, Shier WT et al (2002) Phytotoxicity and mammalian cytotoxicity of macrocyclic trichothecene mycotoxins from Myrothecium verrucaria. Phytochemistry 59(3):309–313PubMedCrossRefGoogle Scholar
  2. Abbas HK, Yoshizawa T, Shier WT (2013) Cytotoxicity and phytotoxicity of trichothecene mycotoxins produced by Fusarium spp.. Toxicon 74:68–75PubMedCrossRefGoogle Scholar
  3. Agrawal M, Yadav P, Lomash V et al (2012) T-2 toxin induced skin inflammation and cutaneous injury in mice. Toxicology 302(2–3):255–265PubMedCrossRefGoogle Scholar
  4. Agrawal M, Bhaskar ASB, Rao PVL (2015) Involvement of mitogen-activated protein kinase pathway in T-2 toxin-induced cell cycle alteration and apoptosis in human neuroblastoma cells. Mol Neurobiol 51:1379–1394PubMedCrossRefGoogle Scholar
  5. Akira S, Takeda K, Kaisho T et al (2001) Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2(8):675–680PubMedCrossRefGoogle Scholar
  6. Alassane-Kpembi I, Puel O, Pinton P et al (2017) Co-exposure to low doses of the food contaminants deoxynivalenol and nivalenol has a synergistic inflammatory effect on intestinal explants. Arch Toxicol 91(7):2677–2687PubMedCrossRefGoogle Scholar
  7. Alcami A, Koszinowski UH (2000) Viral mechanisms of immune evasion. Mol Med Today 6(9):365–372PubMedCrossRefGoogle Scholar
  8. Aleksic B, Bailly S, Draghi M et al (2016) Production of four macrocyclic trichothecenes by Stachybotrys chartarum during its development on different building materials as measured by UPLC-MS/MS. Build Environ 106:265–273CrossRefGoogle Scholar
  9. Allahyari H, Heidari S, Ghamgosha M et al (2017) Immunotoxin: a new tool for cancer therapy. Tumor Biol 39(2):1010428317692226CrossRefGoogle Scholar
  10. Alvarado AG, Lathia JD (2016) Taking a toll on self-renewal: TLR-mediated innate immune signaling in stem cells. Trends Neurosci 39(7):463–471PubMedCrossRefGoogle Scholar
  11. Amagata T, Rath C, Rigot JF et al (2003) Structures and cytotoxic properties of trichoverroids and their macrolide analogues produced by saltwater culture of Myrothecium verrucaria. J Med Chem 46(20):4342–4350PubMedCrossRefGoogle Scholar
  12. Antignani A, FitzGerald D (2013) Immunotoxins: the role of the toxin. Toxins 5(8):1486–1502PubMedCentralPubMedCrossRefGoogle Scholar
  13. Antonissen G, Haesendonck R, Devreese M et al (2016) The impact of deoxynivalenol on pigeon health: occurrence in feed, toxicokinetics and interaction with Salmonellosis. PLoS One 11(12):e0168205PubMedCentralPubMedCrossRefGoogle Scholar
  14. Appell M, Bosma WB (2015) Assessment of the electronic structure and properties of trichothecene toxins using density functional theory. J Hazard Mater 288:113–23PubMedCrossRefGoogle Scholar
  15. Arai KI, Lee F, Miyajima A et al (1990) Cytokines: coordinators of immune and inflammatory responses. Annu Rev Biochem 59:783–836PubMedCrossRefGoogle Scholar
  16. Atroshi F, Rizzo AF, Veijalainen P et al (1994) The effect of dietary exposure to DON and T-2 Toxin on host resistance and serum immunoglobins of normal and mastitic mice. J Anim Physiol Anim N 71(1–5):223–233CrossRefGoogle Scholar
  17. Aupanun S, Phuektes P, Poapolathep S et al (2016) Apoptosis and gene expression in Jurkat human T cells and lymphoid tissues of fusarenon-X-treated mice. Toxicon 123:15–24PubMedCrossRefGoogle Scholar
  18. Aupanun S, Poapolathep S, Giorgi M et al (2017) An overview of the toxicology and toxicokinetics of fusarenon-X, a type B trichothecene mycotoxin. J Vet Med Sci 79(1):6–13PubMedCrossRefGoogle Scholar
  19. Bae HK, Pestka JJ (2008) Deoxynivalenol induces p38 interaction with the ribosome in monocytes and macrophages. Toxicol Sci 105(1):59–66PubMedCrossRefGoogle Scholar
  20. Bae EY, Lee SW, Seong S et al (2015) Inhibitory effects of verrucarin A on tunicamycin-induced ER stress in FaO rat liver cells. Molecules 20:8988–8996PubMedCrossRefGoogle Scholar
  21. Baltriukiene D, Kalvelyte A, Bukelskiene V (2007) Induction of apoptosis and activation of JNK and p38 MAPK pathways in deoxynivalenol-treated cell lines. Altern Lab Anim 35(1):53–59PubMedGoogle Scholar
  22. Bennett JW, Klich M (2003) Mycotoxins. Clin Microbiol Rev 16(3):497–516PubMedCentralPubMedCrossRefGoogle Scholar
  23. Bensassi F, El Golli-Bennour E, Abid-Essefi S et al (2009) Pathway of deoxynivalenol-induced apoptosis in human colon carcinoma cells. Toxicology 264(1–2):104–109PubMedCrossRefGoogle Scholar
  24. Bensassi F, Gallerne C, Sharaf El Dein O et al (2012) Involvement of mitochondria-mediated apoptosis in deoxynivalenol cytotoxicity. Food Chem Toxicol 50(5):1680–1689PubMedCrossRefGoogle Scholar
  25. Betina V (1989) Structure-activity relationships among mycotoxins. Chem Biol Interact 71:105–146PubMedCrossRefGoogle Scholar
  26. Bin-Umer MA, McLaughlin JE, Basu D et al (2011) Trichothecene mycotoxins inhibit mitochondrial translation-implication for the mechanism of toxicity. Toxins 3:1481–1501CrossRefGoogle Scholar
  27. Bin-Umer MA, McLaughlin JE, Butterly MS et al (2014) Elimination of damaged mitochondria through mitophagy reduces mitochondrial oxidative stress and increases tolerance to trichothecenes. PNAS 111(32):11798–11803PubMedCentralPubMedCrossRefGoogle Scholar
  28. Black AP, Jones L, Malavige GN et al (2009) Immune evasion during varicella zoster virus infection of keratinocytes. Clin Exp Dermatol 34(8):941–944CrossRefGoogle Scholar
  29. Bondy GS, Pestka JJ (2000) Immunomodulation by fungal toxins. J Toxicol Env Heal B 3:109–143CrossRefGoogle Scholar
  30. Bouaziz C, Martel C, el Dein OS et al (2009) Fusarial toxin-induced toxicity in cultured cells and in isolated mitochondria involves PTPC-dependent activation of the mitochondrial pathway of apoptosis. Toxicol Sci 110(2):363–375PubMedCrossRefGoogle Scholar
  31. Boyle JP, Parkhouse R, Monie TP (2014) Insights into the molecular basis of the NOD2 signalling pathway. Open Biol 4(12):140178PubMedCentralPubMedCrossRefGoogle Scholar
  32. Brigger I, Dubernet C, Couvreur P (2002) Nanoparticles in cancer therapy and diagnosis. Adv Drug Deliver Rev 54(5):631–651CrossRefGoogle Scholar
  33. Buckland J (2013) Rheumatoid arthritis: autophagy: a dual role in the life and death of RASFs. Nat Rev Rheumatol 9(11):637PubMedCrossRefGoogle Scholar
  34. Cadwell K (2016) Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis. Nat Rev Immunol 16(11):661–675Google Scholar
  35. Cano PM, Seeboth J, Meurens F et al (2013) Deoxynivalenol as a new factor in the persistence of intestinal inflammatory diseases: an emerging hypothesis through possible modulation of Th17-mediated response. PLoS One 8(1):e53647PubMedCentralPubMedCrossRefGoogle Scholar
  36. Choi BK, Jeong SH, Cho JH et al (2013) Effects of oral deoxynivalenol exposure on immune-related parameters in lymphoid organs and serum of mice vaccinated with porcine parvovirus vaccine. Mycotoxin Res 29:185–192PubMedCrossRefGoogle Scholar
  37. Choi YJ, Shin HW, Chun YS et al (2016) Diacetoxyscirpenol as a new anticancer agent to target hypoxia-inducible factor 1. Oncotarget 7(38):62107–62122PubMedCentralPubMedCrossRefGoogle Scholar
  38. Chung YJ, Zhou HR, Pestka JJ (2003) Transcriptional and posttranscriptional roles for p38 mitogen-activated protein kinase in upregulation of TNF-α expression by deoxynivalenol (vomitoxin). Toxicol Appl Pharmacol 193(2):188–201PubMedCrossRefGoogle Scholar
  39. Clarke AJ, Ellinghaus U, Cortini A et al (2015) Autophagy is activated in systemic lupus erythematosus and required for plasmablast development. Ann Rheum Dis 74(5):912–920PubMedCrossRefGoogle Scholar
  40. Cooray R, Jonsson P (1990) Modulation of resistance to mastitis pathogens by pretreatment of mice with T-2 toxin. Food Chem Toxicol 28(10):687–692PubMedCrossRefGoogle Scholar
  41. Cooray R, Lindahl-Kiessling K (1987) Effect of T-2 toxin on the spontaneous antibody-secreting cells and other non-lymphoid cells in the murine spleen. Food Chem Toxicol 25(1):25–29PubMedCrossRefGoogle Scholar
  42. Corrier DE (1991) Mycotoxicosis: mechanisms of immunosuppression. Vet Immunol Immunopathol 30(1):73–87PubMedCrossRefGoogle Scholar
  43. Corrier DE, Ziprin RL (1986a) Enhanced resistance to listeriosis induced in mice by preinoculation treatment with T-2 mycotoxin. Am J Vet Res 47(4):856–859PubMedGoogle Scholar
  44. Corrier DE, Ziprin RL (1986b) Immunotoxic effects of T-2 toxin on cell-mediated immunity to listeriosis in mice:comparison with cyclophosphamide. Am J Vet Res 47(9):1956–1960PubMedGoogle Scholar
  45. Corrier DE, Ziprin RL, Mollenhauer HH (1987a) Modulation of cell-mediated resistance to listeriosis in mice given T-2 toxin. Toxicol Appl Pharmacol 89(3):323–331PubMedCrossRefGoogle Scholar
  46. Corrier DE, Holt PS, Mollenhauer HH (1987b) Regulation of murine macrophage phagocytosis of sheep erythrocytes by T-2 toxin. Am J Vet Res 8(8):1304–1307Google Scholar
  47. Couper KN, Blount DG, Riley EM (2008) IL-10: the master regulator of immunity to infection. J Immunol 180:5771–5777PubMedCrossRefGoogle Scholar
  48. Cozzini P, Dellafiora L (2012) In silico approach to evaluate molecular interaction between mycotoxins and the estrogen receptors ligand binding domain: a case study on zearalenone and its metabolites. Toxicol Lett 214:81–85PubMedCrossRefGoogle Scholar
  49. Cundliffe E, Davies JE (1977) Inhibition of initiation, elongation, and termination of eukaryotic protein synthesis by trichothecene fungal toxins. Antimicrob Agents Ch 11:491–499CrossRefGoogle Scholar
  50. Dai Y, Hu S (2016) Recent insights into the role of autophagy in the pathogenesis of rheumatoid arthritis. Rheumatology 55(3):403–410PubMedGoogle Scholar
  51. Das DN, Naik PP, Nayak A et al (2016) Bacopa monnieri-induced protective autophagy inhibits Benzo[a]pyrene-mediated apoptosis. Phytother Res 30(11):1794–1801PubMedCrossRefGoogle Scholar
  52. de Carvalho MP, Weich H, Abraham WR (2016) Macrocyclic trichothecenes as antifungal and anticancer compounds. Curr Med Chem 23(1):23–25PubMedCrossRefGoogle Scholar
  53. Deeb D, Gao X, Liu Y et al (2016) The inhibition of cell proliferation and induction of apoptosis in pancreatic ductal adenocarcinoma cells by verrucarin A, a macrocyclic trichothecene, is associated with the inhibition of Akt/NF-кB/mTOR prosurvival signaling. Int J Oncol 49:1139–1147PubMedCrossRefGoogle Scholar
  54. Dellafiora L, Galaverna G, Dall’Asta C (2017) In silico analysis sheds light on the structural basis underlying the ribotoxicity of trichothecenes—a tool for supporting the hazard identification process. Toxicol Lett 270:80–87PubMedCrossRefGoogle Scholar
  55. Deng Y, Wang Y, Zhang X et al (2017) Effects of T-2 toxin on pacific white shrimp litopenaeus vannamei: growth, and antioxidant defenses and capacity and histopathology in the hepatopancreas. J Aquat Anim Health 29:15–25PubMedCrossRefGoogle Scholar
  56. Desjardins AE, McCormick SP, Appell M (2007) Structure-activity relationships of trichothecene toxins in an Arabidopsis thaliana leaf assay. J Agric Food Chem 55(16):6487–6492PubMedCrossRefGoogle Scholar
  57. Diamond M, Reape TJ, Rocha O et al (2013) The Fusarium mycotoxin deoxynivalenol can inhibit plant apoptosis-like programmed cell death. PLoS One 8(7):e69542PubMedCentralPubMedCrossRefGoogle Scholar
  58. Du RH, Cui JT, Wang T et al (2012) Trichothecin induces apoptosis of HepG2 cells via caspase-9 mediated activation of the mitochondrial death pathway. Toxicon 59:143–150PubMedCrossRefGoogle Scholar
  59. Fang H, Wu Y, Guo J et al (2012) T-2 toxin induces apoptosis in differentiated murine embryonic stem cells through reactive oxygen species-mediated mitochondrial pathway. Apoptosis 17(8):895–907PubMedCrossRefGoogle Scholar
  60. Fang H, Cong L, Zhi Y et al (2016) T-2 toxin inhibits murine ES cells cardiac differentiation and mitochondrial biogenesis by ROS and p-38 MAPK-mediated pathway. Toxicol Lett 258:259–266PubMedCrossRefGoogle Scholar
  61. Fimiani V, Richetti A (1993) Antitumor effect of a mycotoxin: rubratoxin B. Chemotherapy 39(1):59–62PubMedCrossRefGoogle Scholar
  62. Finocchiaro G (2017) TLRgeting evasion of immune pathways in Glioblastoma. Cell Stem Cell 20(4):422–424PubMedCrossRefGoogle Scholar
  63. Flannery BM, He K, Pestka JJ (2013) Deoxynivalenol-induced weight loss in the diet-induced obese mouse is reversible and PKR-independent. Toxicol Lett 221(1):9–14PubMedCrossRefGoogle Scholar
  64. Forsell JH, Pestka JJ (1985) Relation of 8-ketotrichothecene and zearalenone analog structure to inhibition of mitogen-induced human lymphocyte blastogenesis. Appl Environ Microbiol 50(5):1304–1307PubMedCentralPubMedGoogle Scholar
  65. Garreau de Loubresse N, Prokhorova I, Holtkamp W et al (2014) Structural basis for the inhibition of the eukaryotic ribosome. Nature 513:517–522PubMedCrossRefGoogle Scholar
  66. Gauthier T, Waché Y, Laffitte J et al (2013) Deoxynivalenol impairs the immune functions of neutrophils. Mol Nutr Food Res 57(6):1026–1036PubMedCrossRefGoogle Scholar
  67. Gojis O, Rudraraju B, Alifrangis C et al (2010) The role of steroid receptor coactivator-3 (SRC-3) in human malignant disease. EJSO 36(3):224–229PubMedCrossRefGoogle Scholar
  68. Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32(5):593–604PubMedCrossRefGoogle Scholar
  69. Gosselina E, Denisb O, Cauwenbergec AV et al (2012) Quantification of the trichothecene Verrucarin-A in environmental samples using an antibody-based spectroscopic biosensor. Sensor Actuat B 10:166–167Google Scholar
  70. Gray JS, Bae HK, Li JC et al (2008) Double-stranded RNA-activated protein kinase mediates induction of interleukin-8 expression by deoxynivalenol, Shiga toxin 1, and ricin in monocytes. Toxicol Sci 105(2):322–330PubMedCentralPubMedCrossRefGoogle Scholar
  71. Grove JF, Hosken M (1975) The larvicidal activity of some 12,13-epoxytrichothece-9-enes. Biochem Pharmacol 24:959–962PubMedCrossRefGoogle Scholar
  72. Gu W, Cui R, Ding T et al (2017) Simvastatin alleviates airway inflammation and remodelling through up-regulation of autophagy in mouse models of asthma. Respirology 22(3):533–541PubMedCrossRefGoogle Scholar
  73. Guerrero-Netro HM, Chorfi Y, Price CA (2015) Effects of the mycotoxin deoxynivalenol on steroidogenesis and apoptosis in granulosa cells. Reproduction 149(6):555–561PubMedCrossRefGoogle Scholar
  74. Han J, Wang T, Fu L et al (2015) Altered oxidative stress, apoptosis/autophagy, and epigenetic modifications in Zearalenone-treated porcine oocytes. Toxicol Res 4(5):1184–1194Google Scholar
  75. Han J, Wang QC, Zhu CC et al (2016) Deoxynivalenol exposure induces autophagy/apoptosis and epigenetic modification changes during porcine oocyte maturation. Toxicol Appl Pharm 300:70–76CrossRefGoogle Scholar
  76. Hara KY, Sugita KY, Kasuga F et al (1996) Effects of deoxynivalenol on Salmonella enteritidis infection. Jsm Mycotoxins 42(42):51–55CrossRefGoogle Scholar
  77. Harris AL (2002) Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47PubMedCrossRefGoogle Scholar
  78. He K, Zhou HR, Pestka JJ (2012a) Targets and intracellular signaling mechanisms for deoxynivalenol-induced ribosomal RNA cleavage. Toxicol Sci 127(2):382–390PubMedCentralPubMedCrossRefGoogle Scholar
  79. He ZJ, Zhu FY, Li SS et al (2017) Inhibiting ROS-NF-kappaB-dependent autophagy enhanced brazilin-induced apoptosis in head and neck squamous cell carcinoma. Food Chemical Toxicol 101:55–66CrossRefGoogle Scholar
  80. Hirano S, Kataoka T (2013) Deoxynivalenol induces ectodomain shedding of TNF receptor 1 and thereby inhibits the TNF-α-induced NF-κB signaling pathway. Eur J Pharmacol 701(1–3):144–151PubMedCrossRefGoogle Scholar
  81. Hou R, Jiang C, Zheng Q et al (2015) The AreA transcription factor mediates the regulation of deoxynivalenol (DON) synthesis by ammonium and cyclic adenosine monophosphate (cAMP) signalling in Fusarium graminearum. Molecul Plant Pathol 16(9):987–999CrossRefGoogle Scholar
  82. Hromas RA, Yung WK (1986) Anguidine potentiates cis-platinum in human brain tumor cells. J Neurooncol 3:343–348PubMedCrossRefGoogle Scholar
  83. Huang C, Zhang Q, Feng W (2015) Regulation and evasion of antiviral immune responses by porcine reproductive and respiratory syndrome virus. Virus Res 202:101–111PubMedCrossRefGoogle Scholar
  84. Hwang DW, So KS, Kim SC et al (2017) Autophagy induced by CX-4945, a casein kinase 2 inhibitor, enhances apoptosis in pancreatic cancer cell lines. Pancreas 46(4):575–581PubMedCrossRefGoogle Scholar
  85. Hymery N, Léon K, Carpentier FG et al (2009) T-2 toxin inhibits the differentiation of human monocytes into dendritic cells and macrophages. Toxicol in Vitro 23:509–519PubMedCrossRefGoogle Scholar
  86. Iida A, Konishi K, Kubo H et al (1996) Trichothecinols A, B and C, potent anti-tumor promoting sesquiterpenoids from the fungus Trichothecium roseum. Tetrahedron Lett 37(51):9219–9220CrossRefGoogle Scholar
  87. Ikawa M, Carr C, Tatsuno T (1985) Trichothecene structure and toxicity to the green alga Chlorella pyrenoidosa. Toxicon 23(3):535–537PubMedCrossRefGoogle Scholar
  88. Islam Z, Nagase M, Yoshizawa T et al (1988) T-2 toxin induces thymic apoptosis in vivo in mice. Toxicol Appl Pharmacol 148(2):205–214CrossRefGoogle Scholar
  89. Islam Z, Gray JS, Pestka JJ (2006) p38 Mitogen-activated protein kinase mediates IL-8 induction by the ribotoxin deoxynivalenol in human monocytes. Toxicol Appl Pharmacol 213(3):235–244PubMedCrossRefGoogle Scholar
  90. Islam MR, Roh YS, Kim J et al (2013) Differential immune modulation by deoxynivalenol (vomitoxin) in mice. Toxicol Lett 221(2):152–163PubMedCrossRefGoogle Scholar
  91. Ito Y, Yanase S, Fujita J et al (1981) A short-term in vitro assay for promoter substances using human lymphoblastoid cells latently infected with Epstein-Barr virus. Cancer Lett 13(1):29–37Google Scholar
  92. Jarvis BB, Stahly GP, Curtis CR (1978) Antitumor activity of fungal metabolites: verrucarin beta-9, 10-epoxides. Cancer Treatment Rep 62(10):1585–1586Google Scholar
  93. Jarvis BB, Stahly GP, Pavanasasivam G et al (1980) Antileukemic compounds derived from the chemical modification of macrocyclic trichothecenes. 1. Derivatives of verrucarin A. J Med Chem 23(9):1054–1058PubMedCrossRefGoogle Scholar
  94. Jarvis BB, Eppley RM, Mazolla EP (1983) Chemistry and bioproduction of macrocyclic trichothecenes. In: Ueno Y (ed) Trichothecenes—chemical, biological and toxicological aspects. Elsevier, Amsterdam, pp 20–38Google Scholar
  95. Jarvis BB, Midiwo JO, Mazzola EP (1984) Antileukemic compounds derived by chemical modification of macrocyclic trichothecenes. 2. Derivatives of roridins A and H and verrucarins A and J. J Med Chem 27(2):239–244PubMedCrossRefGoogle Scholar
  96. Jayasooriya RG, Moon DO, Park SR et al (2013a) Combined treatment with verrucarin A and tumor necrosis factor-α sensitizes apoptosis by overexpression of nuclear factor-kappaB-mediated Fas. Environ Toxicol Pharmacol 36(2):303–310PubMedCrossRefGoogle Scholar
  97. Jayasooriya RG, Moon DO, Yun SG et al (2013b) Verrucarin A enhances TRAIL-induced apoptosis via NF-κB-mediated Fas overexpression. Food Chem Toxicol 55:1–7PubMedCrossRefGoogle Scholar
  98. Jeker N, Tamm C (1988) Synthesis of new unnatural macrocyclic trichothecenes: 4-epiverrucarin A. Helv Chim Acta 1:1904CrossRefGoogle Scholar
  99. Jia Q, Zhou HR, Shi Y et al (2006) Docosahexaenoic acid consumption inhibits deoxynivalenol-induced CREB/ATF1 activation and IL-6 gene transcription in mouse macrophages. J Nutr 136(2):366–372PubMedGoogle Scholar
  100. Jun DY, Kim JS, Park HS et al (2007) Cytotoxicity of diacetoxyscirpenol is associated with apoptosis by activation of caspase-8 and interruption of cell cycle progression by down-regulation of cdk4 and cyclin B1 in human Jurkat T cells. Toxicol Appl Pharmacol 15:190–201CrossRefGoogle Scholar
  101. Kanai K, Kondo E (1984) Decreased resistance to mycobacterial infection in mice fed a trichothecene compound (T-2 toxin). Japan J Med Sci Biol 37(2):97–104CrossRefGoogle Scholar
  102. Karlovsky P (2011) Biological detoxification of the mycotoxin deoxynivalenol and its use in genetically engineered crops and feed additives. Appl Microbiol Biotechnol 91:491–504PubMedCentralPubMedCrossRefGoogle Scholar
  103. Katika MR, Hendriksen PJ, van Loveren H et al (2015) Characterization of the modes of action of deoxynivalenol (DON) in the human Jurkat T-cell line. J Immunotoxicol 12(3):206–216PubMedCrossRefGoogle Scholar
  104. Ke PY (2017) Horning cell self-digestion: autophagy wins the 2016 Nobel Prize in physiology or medicine. Biomed J 40(1):5–8PubMedCrossRefGoogle Scholar
  105. Ke Q, Costa M (2006) Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol 70(5):1469–1480PubMedCrossRefGoogle Scholar
  106. Kim HS, Lee MS (2007) STAT1 as a key modulator of cell death. Cell Signal 19:454–465PubMedCrossRefGoogle Scholar
  107. Kim EY, Moudgil KD (2017) Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines. Cytokine 98:87–96PubMedCrossRefGoogle Scholar
  108. Kojima S, Nakamura N, Ueno Y et al (1993) Anti-tumor activity of T-2 Toxin-conjugated A7 monoclonal antibody (T-2-A7 MoAb) against human colon carcinoma. Nat Toxins 1:209–215PubMedCrossRefGoogle Scholar
  109. Königs M, Schwerdt G, Gekle M et al (2008) Effects of the mycotoxin deoxynivalenol on human primary hepatocytes. Mol Nutr Food Res 2(7):830–839CrossRefGoogle Scholar
  110. Konishi K, Iida A, Kaneko M et al (2003) Cancer preventive potential of trichothecenes from Trichothecium roseum. Bioorg Med Chem 1:2511–2518CrossRefGoogle Scholar
  111. Kubena LF, Bailey RH, Byrd JA et al (2001) Cecal volatile fatty acids and broiler chick susceptibility to Salmonella typhimurium colonization as affected by aflatoxins and T-2 toxin. Poult Sci 80(4):411–417PubMedCrossRefGoogle Scholar
  112. Kubo M, Motomura Y (2012) Transcriptional regulation of the anti-inflammatory cytokine IL-10 in acquirec immune cells. Front Immuno 3:275CrossRefGoogle Scholar
  113. Kugler KG, Jandric Z, Beyer R et al (2016) Ribosome quality control is a central protection mechanism for yeast exposed to deoxynivalenol and trichothecin. BMC Genomics 17:417PubMedCentralPubMedCrossRefGoogle Scholar
  114. Kwon O, Soung NK, Thimmegowda NR et al (2012) Patulin induces colorectal cancer cells apoptosis through EGR-1 dependent ATF3 up-regulation. Cell Signal 24(4):943–950PubMedCrossRefGoogle Scholar
  115. LaRock CN, Nizet V (2015) Inflammasome/IL-1 beta responses to streptococcal pathogens. Front Immuno 6:518CrossRefGoogle Scholar
  116. Lee KH, Nishimura S, Matsunaga S et al (2006) Induction of a ribotoxic stress response that stimulates stress-activated protein kinases by 13-deoxytedanolide, an antitumor marine macrolide. Biosci Biotechnol Biochem 70(1):161–171PubMedCrossRefGoogle Scholar
  117. Lessard M, Savard C, Deschene K et al (2015) Impact of deoxynivalenol (DON) contaminated feed on intestinal integrity and immune response in swine. Food Chem Toxicol 80:7–16PubMedCrossRefGoogle Scholar
  118. Li M, Cuff CF, Pestka J (2005) Modulation of murine host response to enteric reovirus infection by the trichothecene deoxynivalenol. Toxicol Sci 87(1):134–145PubMedCrossRefGoogle Scholar
  119. Li M, Cuff CF, Pestka JJ (2006a) T-2 toxin impairment of enteric reovirus clearance in the mouse associated with suppressed immunoglobulin and IFN-γ responses. Toxic Appl Pharmacol 214:318–325PubMedCrossRefGoogle Scholar
  120. Li M, Harkema JR, Islam Z et al (2006b) T-2 toxin impairs murine immune response to respiratory reovirus and exacerbates viral bronchiolitis. Toxic Appl Pharmacol 7:76–85CrossRefGoogle Scholar
  121. Li SJ, Pasmans F, Croubels S et al (2013) T-2 toxin impairs antifungal activities of chicken macrophages against Aspergillus fumigatus conidia but promotes the pro-inflammatory responses. Avian Pathol 42(5):457–463PubMedCrossRefGoogle Scholar
  122. Li D, Ma H, Ye Y et al (2014) Deoxynivalenol induces apoptosis in mouse thymic epithelial cells through mitochondria-mediated pathway. Environ Toxicol Pharmacol 38(1):163–171PubMedCrossRefGoogle Scholar
  123. Li DY, Han J, Guo X et al (2016) The effects of T-2 toxin on the prevalence and development of Kashin-Beck disease in China:a meta-analysis and systematic review. Toxicology Res 5(3):731–751CrossRefGoogle Scholar
  124. Li B, Lu M, Jiang XX et al (2017) Inhibiting reactive oxygen species-dependent autophagy enhanced baicalein-induced apoptosis in oral squamous cell carcinoma. J Nat Med 71(2):433–441PubMedCrossRefGoogle Scholar
  125. Liu J, Wang L, Guo X et al (2014a) The role of mitochondria in T-2 toxin-induced human chondrocytes apoptosis. PLoS One 9(9):e108394PubMedCentralPubMedCrossRefGoogle Scholar
  126. Liu J, Simmons SO, Pei R (2014b) Regulation of IL-8 promoter activity by verrucarin A in human monocytic THP-1 cells. J Toxicol Environ Health A 77(19):1125–1140PubMedCrossRefGoogle Scholar
  127. Liu YN, Wang YX, Liu XF et al (2015) Citreoviridin induces ROS-dependent autophagic cell death in human liver HepG2 cells. Toxicon 95:30–37PubMedCrossRefGoogle Scholar
  128. Liu Y, Gao X, Deeb D et al (2016) Mycotoxin verrucarin A inhibits proliferation and induces apoptosis in prostate cancer cells by inhibiting prosurvival Akt/NF-kB/mTOR signaling. J Exp Ther Oncol 11(4):251–260PubMedGoogle Scholar
  129. Liu X, Guo P, Liu A et al (2017a) Nitric oxide (NO)-mediated mitochondrial damage plays a critical role in T-2 toxin-induced apoptosis and growth hormone deficiency in rat anterior pituitary GH3 cells. Food Chem Toxicol 102:11–23PubMedCrossRefGoogle Scholar
  130. Liu X, Huang D, Guo P et al (2017b) PKA/CREB and NF-κB pathway regulates AKNA transcription: A novel insight into T-2 toxin-induced inflammation and GH deficiency in GH3 cells. Toxicology 392:81–95Google Scholar
  131. Lucioli J, Pinton P, Callu P et al (2013) The food contaminant deoxynivalenol activates the mitogen activated protein kinases in the intestine:Interest of ex vivo models as an alternative to in vivo experiments. Toxicon 66:31–36PubMedCrossRefGoogle Scholar
  132. Lum JJ, DeBerardinis RJ, Thompson CB (2005) Autophagy in metazoans:cell survival in the land of plenty. Nature Rev Mol Cell Biol 6:439–448CrossRefGoogle Scholar
  133. Ma YN, Zhang AH, Shi ZY et al (2012) A mitochondria-mediated apoptotic pathway induced by deoxynivalenol in human colon cancer cells. Toxicol in Vitro 26:414–420PubMedCrossRefGoogle Scholar
  134. Madhyastha MS, Marquardt RR, Abramson D (1994) Structure-activity relationships and interactions among trichothecene mycotoxins as assessed by yeast bioassay. Toxicon 32(9):1147–1152PubMedCrossRefGoogle Scholar
  135. Mahmuda A, Bande F, Al-Zihiry KJK et al (2017) Monoclonal antibodies: a review of therapeutic applications and future prospects. Trop J Pharm Res 16(3):713–722CrossRefGoogle Scholar
  136. Maiuri C, Zalckvar E, Kimchi A et al (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nature Rev Mol Cell Biol 8:741–752CrossRefGoogle Scholar
  137. Marzocco S, Russo R, Bianco G et al (2009) Pro-apoptotic effects of nivalenol and deoxynivalenol trichothecenes in J774A.1 murine macrophages. Toxicol Lett 89(1):21–26CrossRefGoogle Scholar
  138. Mbandi E, Pestka JJ (2006) Deoxynivalenol and satratoxin G potentiate proinflammatory cytokine and macrophage inhibitory protein 2 induction by Listeria and Salmonella in the macrophage. J Food Prot 69(6):1334–1339PubMedCrossRefGoogle Scholar
  139. McCormick SP, Stanley AM, Stover NA et al (2011) Trichothecenes: from simple to complex mycotoxins. Toxins (Basel) 3(7):802–814CrossRefGoogle Scholar
  140. Melero I, Hervas-Stubbs S, Glennie M et al (2007) Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer 7(2):95–106PubMedCrossRefGoogle Scholar
  141. Messer JS (2017) The cellular autophagy/apoptosis checkpoint during inflammation. Cell Mol Life Sci 74(7):1281–1296PubMedCrossRefGoogle Scholar
  142. Mikami O, Yamaguchi H, Murata H et al (2010) Induction of apoptotic lesions in liver and lymphoid tissues and modulation of cytokine mRNA expression by acute exposure to deoxynivalenol in piglets. J Vet Sci 11(2):107–113PubMedCentralPubMedCrossRefGoogle Scholar
  143. Miller K, Atkinson HA (1986) The in vitro effects of trichothecenes on the immune system. Food Chem Toxicol 24(6–7):545–549PubMedCrossRefGoogle Scholar
  144. Mishra S, Tripathi A, Chaudhari BP et al (2014) Deoxynivalenol induced mouse skin cell proliferation and inflammation via MAPK pathway. Toxicol Appl Pharmacol 279(2):186–197PubMedCrossRefGoogle Scholar
  145. Moon Y, Pestka JJ (2002) Vomitoxin-induced cyclooxygenase-2 gene expression in macrophages mediated by activation of ERK and p38 but not JNK mitogen-activation protein kinases. Toxicol Sci 69:373–382PubMedCrossRefGoogle Scholar
  146. Moon DO, Asami Y, Long H et al (2013) Verrucarin A sensitizes TRAIL-induced apoptosis via the upregulation of DR5 in an eIF2α/CHOP-dependent manner. Toxicol In Vitro 27(1):257–263PubMedCrossRefGoogle Scholar
  147. Mu P, Xu M, Zhang L et al (2013) Proteomic changes in chicken primary hepatocytes exposed to T-2 toxin are associated with oxidative stress and mitochondrial enhancement. Proteomics 13(21):3175–3188PubMedCrossRefGoogle Scholar
  148. Muenst S, Läubli H, Soysal SD et al (2016) The immune system and cancer evasion strategies: therapeutic concepts. J Intern Med 79(6):541–562CrossRefGoogle Scholar
  149. Murakami Y, Okuda T, Shindo K et al (2001) New macrocyclic trichothecene group antitumor antibiotics, from Myrothecium verrucaria. J Antibiot 54(11):980–983PubMedCrossRefGoogle Scholar
  150. Nagar R (2017) Autophagy: a brief overview in perspective of dermatology. Indian J Dermatol Venereol Leprol 83(3):290–297PubMedCrossRefGoogle Scholar
  151. Nawrocki ST, Carew JS, Dunner, KJr et al (2005) Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. Cancer Res 65(24):11510–11519PubMedCrossRefGoogle Scholar
  152. Nelsen CJ, Murtaugh MP, Faaberg KS (1999) Porcine reproductive and respiratory syndrome virus comparison:divergent evolution on two continents. J Virol 73(1):270–280PubMedCentralPubMedGoogle Scholar
  153. Neumann EJ, Kliebenstein JB, Johnson CD et al (2005) Assessment of the economic impact of porcine reproductive and respiratory syndrome on swine production in the United States. J Am Vet Med Assoc 227(3):385–392PubMedCrossRefGoogle Scholar
  154. Ngampongsa S, Hanafusa M, Ando K et al (2013) Toxic effects of T-2 toxin and deoxynivalenol on the mitochondrial electron transport system of cardiomyocytes in rats. J Toxicol Sci 38(3):495–502PubMedCrossRefGoogle Scholar
  155. Nibert ML, Margraf RL, Coombs KM (1996) Nonrandom segregation of parental alleles in reovirus reassortants. J Virol 70(10):7295–7300PubMedCentralPubMedGoogle Scholar
  156. Oda T, Xu J, Ukai K et al (2010) 12′-Hydroxyl group remarkably reduces Roridin E cytotoxicity. Mycoscience 51:317–320CrossRefGoogle Scholar
  157. Oeckinghaus A, Hayden MS, Ghosh S (2011) Crosstalk in NF-kappa B signaling pathways. Nat Immunol 12(8):695–708PubMedCrossRefGoogle Scholar
  158. Ohtani K, Murakami H, Shibuya O et al (1990) Antitumor activity of T-2 toxin-conjugated monoclonal antibody to murine thymoma. Japan J Exp Med 60(2):57–65Google Scholar
  159. Opriessnig T, Meng XJ, Halbur PG (2007) Porcine circovirus type 2 associated disease: update on current terminology, clinical manifestations, pathogenesis, diagnosis, and intervention strategies. J Vet Diagn Invest 19(6):591–615PubMedCrossRefGoogle Scholar
  160. Orvedahl A, Macpherson S Jr RS et al (2010) Autophagy protects against sindbis virus infection of the central nervous system. Cell Host Microbe 7(2):115–127PubMedCentralPubMedCrossRefGoogle Scholar
  161. Pace JG, Watts MR, Canterbury WJ (1988) T-2 mycotoxin inhibits mitochondrial protein synthesis. Toxicon 26:77–85PubMedCrossRefGoogle Scholar
  162. Pai RK, Convery M, Hamilton TA et al (2003) Inhibition of IFN-gamma-induced class II transactivator expression by a 19-kDa lipoprotein from Mycobacterium tuberculosis: a potential mechanism for immune evasion. J Immunol 171(1):175–184PubMedCrossRefGoogle Scholar
  163. Palanivel K, Kanimozhi V, Kadalmani B et al (2013) Verrucarin A, a protein synthesis inhibitor, induces growth inhibition and apoptosis in breast cancer cell lines MDA-MB-231 and T47D. Biotechnol Lett 35(9):1395–1403PubMedCrossRefGoogle Scholar
  164. Palanivel K, Kanimozhi V, Kadalmani B (2014a) Verrucarin A alters cell-cycle regulatory proteins and induces apoptosis through reactive oxygen species-dependent p38MAPK activation in the human breast cancer cell line MCF-7. Tumour Biol 35(10):10159–10167PubMedCrossRefGoogle Scholar
  165. Palanivel K, Kanimozhi V, Kadalmani B et al (2014b) Verrucarin A induces apoptosis through ROS-mediated EGFR/MAPK/Akt signaling pathways in MDA-MB-231 breast cancer cells. J Cell Biochem 115(11):2022–2032PubMedGoogle Scholar
  166. Pan X, Whitten DA, Wu M et al (2013a) Global protein phosphorylation dynamics during deoxynivalenol-induced ribotoxic stress response in the macrophage. Toxicol Appl Pharmacol 268(2):201–211PubMedCentralPubMedCrossRefGoogle Scholar
  167. Pan X, Whitten DA, Wu M et al (2013b) Early phosphoproteomic changes in the mouse spleen during deoxynivalenol-induced ribotoxic stress. Toxicol Sci 135(1):129–143PubMedCentralPubMedCrossRefGoogle Scholar
  168. Pan X, Whitten DA, Wilkerson CG et al (2014) Dynamic changes in ribosome-associated proteome and phosphoproteome during deoxynivalenol-induced translation inhibition and ribotoxic stress. Toxicol Sci 138(1):217–233PubMedCrossRefGoogle Scholar
  169. Parker BS, Slaney CY, Bidwell BN et al (2011) Tumor cell induced immune evasion via loss of Type I IFN signalling promotes breast cancer metastasis. Cytokine 56:102CrossRefGoogle Scholar
  170. Payros D, Alassane-Kpembi I, Pierron A et al (2016) Toxicology of deoxynivalenol and its acetylated and modified forms. Arch Toxicol 90(12):2931–2957PubMedCrossRefGoogle Scholar
  171. Pestka JJ (2003) Deoxynivalenol-induced IgA production and IgA nephropathy-aberrant mucosal immune response with systemic repercussions. Toxicol Lett 140:287–295PubMedCrossRefGoogle Scholar
  172. Pestka JJ (2010) Deoxynivalenol: mechanisms of action, human exposure, and toxicological relevance. Arch Toxicol 4(9):663–679CrossRefGoogle Scholar
  173. Pestka JJ, Tai JH, Wlrr MF et al (1987) Suppression of immune response in the b6c3fi mouse after dietary exposure to the Fusarium mycotoxins deoxynivalenol (vomitoxin) and zearalenone. Food Chem Toxic 25(4):297–304CrossRefGoogle Scholar
  174. Pestka JJ, Yan D, King LE (1994) Flow cytometric analysis of the effects of in vitro exposure to vomitoxin (deoxynivalenol) on apoptosis in murine T, B and IgA+ cells. Food Chem Toxicol 32(12):1125–1136PubMedCrossRefGoogle Scholar
  175. Pestka JJ, Zhou HR, Moon Y et al (2004) Cellular and molecular mechanisms for immune modulation by deoxynivalenol and other trichothecenes: unraveling a paradox. Toxicol Lett 153(1):61–73PubMedCrossRefGoogle Scholar
  176. Pham DL, Ban GY, Kim SH et al (2017) Neutrophil autophagy and extracellular DNA traps contribute to airway inflammation in severe asthma. Clin Exp Allergy 47(1):57–70PubMedCrossRefGoogle Scholar
  177. Pierdominici M, Vomero M, Barbati C et al (2012) Role of autophagy in immunity and autoimmunity, with a special focus on systemic lupus erythematosus. FASEB J 26(4):1400–1412PubMedCrossRefGoogle Scholar
  178. Pierron A, Mimoun S, Murate LS et al (2016) Microbial biotransformation of DON: molecular basis for reduced toxicity. Sci Rep 6:29105PubMedCentralPubMedCrossRefGoogle Scholar
  179. Pietsch C, Katzenback BA, Garcia-Garcia E et al (2015) Acute and subchronic effects on immune responses of carp (Cyprinus carpio L.) after exposure to deoxynivalenol (DON) in feed. Mycotoxin Res 31(3):151–164PubMedCrossRefGoogle Scholar
  180. Pinton P, Oswald IP (2014) Effect of deoxynivalenol and other Type B trichothecenes on the intestine: a review. Toxins (Basel) 6(5):1615–1643CrossRefGoogle Scholar
  181. Pinton P, Accensi F, Beauchamp E et al (2008) Ingestion of deoxynivalenol (DON) contaminated feed alters the pig vaccinal immune responses. Toxicol Lett 177(3):215–222PubMedCrossRefGoogle Scholar
  182. Pinton P, Braicu C, Nougayrede JP et al (2010) Deoxynivalenol impairs porcine intestinal barrier function and decreases the protein expression of claudin-4 through a mitogen-acitivated protein kinase-dependent mechanism. J Nutr 140:1956–1962PubMedCrossRefGoogle Scholar
  183. Pinton P, Tsybulskyy D, Lucioli J et al (2012) Toxicity of deoxynivalenol and its acetylated derivatives on the intestine: differential effects on morphology, barrier function, tight junction proteins, and mitogen-activated protein kinases. Toxicol Sci 130(1):180–190PubMedCrossRefGoogle Scholar
  184. Pinton P, Graziani F, Pujol A et al (2015) Deoxynivalenol inhibits the expression by goblet cells of intestinal mucins through a PKR and MAP kinase dependent repression of the resistin-like molecule β. Mol Nutr Food Res 59(6):1076–1087PubMedCrossRefGoogle Scholar
  185. Reinhart D, Kunert R (2015) Upstream and downstream processing of recombinant IgA. Biotechnol Lett 37(2):241–251PubMedCrossRefGoogle Scholar
  186. Ren Z, Wang Y, Deng H et al (2015) Deoxynivalenol-induced cytokines and related genes in concanavalin A-stimulated primary chicken splenic lymphocytes. Toxicol in Vitro 29(3):558–563PubMedCrossRefGoogle Scholar
  187. Rogers LM, Veeramani S, Weiner GJ (2014) Complement in monoclonal antibody therapy of cancer. Immunol Res 59(1–3):203–210PubMedCentralPubMedCrossRefGoogle Scholar
  188. Roh HJ, Sung HW, Kwon HM (2006) Effects of DDA, CpG-ODN, and plasmid-encoded chicken IFN-gamma on protective immunity by a DNA vaccine against IBDV in chickens. J Vet Sci 7(4):361–368PubMedCentralPubMedCrossRefGoogle Scholar
  189. Ryan HE, Poloni M, McNulty W et al (2000) Hypoxia-inducible factor-1alpha is a positive factor in solid tumor growth. Cancer Res 60(15):4010–4015PubMedGoogle Scholar
  190. Ryu SM, Lee HM, Song EG et al (2017) Antiviral activities of trichothecenes isolated from Trichoderma albolutescens against Pepper Mottle Virus. J Agric Food Chem 65(21):4273–4279PubMedCrossRefGoogle Scholar
  191. Salceda S, Caro J (1997) Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. J Biol Chem 272(36):22642–22647PubMedCrossRefGoogle Scholar
  192. Salem M, Ammitzboell M, Nys K et al (2015) ATG16L1: a multifunctional susceptibility factor in Crohn disease. Autophagy 11(4):585–594PubMedCentralPubMedCrossRefGoogle Scholar
  193. Salem IB, Boussabbeh M, Da Silva JP et al (2017) SIRT1 protects cardiac cells against apoptosis induced by zearalenone or its metabolites alpha- and beta-zearalenol through an autophagy-dependent pathway. Toxicol Appl Pharm 314:82–90CrossRefGoogle Scholar
  194. Samrat SK, Vedi S, Singh S et al (2015) Immunization with recombinant adenoviral vectors expressing HCV core or F proteins leads to T cells with reduced effector molecules granzyme B and IFN-γ: a potential new strategy for immune evasion in HCV infection. Viral Immunol 28(6):309–324PubMedCrossRefGoogle Scholar
  195. Savard C, Pinilla V, Provost C et al (2014a) In vivo effect of deoxynivalenol (DON) naturally contaminated feed on porcine reproductive and respiratory syndrome virus (PRRSV) infection. Vet Microbiol 174(3–4):419–426PubMedCrossRefGoogle Scholar
  196. Savard C, Pinilla V, Provost C et al (2014b) In vitro effect of deoxynivalenol (DON) mycotoxin on porcine reproductive and respiratory syndrome virus replication. Food Chem Toxicol 65:219–226PubMedCrossRefGoogle Scholar
  197. Savard C, Gagnona CA, Chorfi Y (2015a) Deoxynivalenol (DON) naturally contaminated feed impairs theimmune response induced by porcine reproductive and respiratorysyndrome virus (PRRSV) live attenuated vaccine. Vaccine 33:3881–3886PubMedCrossRefGoogle Scholar
  198. Savard C, Provost C, Alvarez F et al (2015b) Effect of deoxynivalenol (DON) mycotoxin on in vivo and in vitro porcine circovirus type 2 infections. Vet Microbiol 176(3–4):257–267PubMedCrossRefGoogle Scholar
  199. Seeboth J, Solinhac R, Oswald IP et al (2012) The fungal T-2 toxin alters the activation of primary macrophages induced by TLR-agonists resulting in a decrease of the inflammatory response in the pig. Vet Res 43:35PubMedCentralPubMedCrossRefGoogle Scholar
  200. Semenza GL (2010) Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncongene 29(5):625–634CrossRefGoogle Scholar
  201. Sergent T, Parys M, Garsou S et al (2006) Deoxynivalenol transport across human intestinal Caco-2 cells and its effects on cellular metabolism at realistic intestinal concentrations. Toxicol Lett 164(2):167–176PubMedCrossRefGoogle Scholar
  202. Shi Y, Pestka JJ (2009) Mechanisms for suppression of interleukin-6 expression in peritoneal macrophages from docosahexaenoic acid-fed mice. J Nutr Biochem 20(5):358–368PubMedCrossRefGoogle Scholar
  203. Shi Y, Porter K, Parameswaran N et al (2009) Role of GRP78/BiP degradation and ER stress in deoxynivalenol-induced interleukin-6 upregulation in the macrophage. Toxicol Sci 109(2):247–255PubMedCentralPubMedCrossRefGoogle Scholar
  204. Shifrin VI, Anderson P (1999) Trichothecene mycotoxins trigger a ribotoxic stress response that activates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase and induces apoptosis. J Biol Chem 274(20):13985–13992PubMedCrossRefGoogle Scholar
  205. Smitka TA, Bunge RH, Bloem RJ et al (1984) Two new trichothecenes, PD 113,325 and PD 113,326. J Antibiot (Tokyo) 37(8):823–828Google Scholar
  206. Solhaug A, Torgersen ML, Holme JA et al (2014) Autophagy and senescence, stress responses induced by the DNA-damaging mycotoxin alternariol. Toxicology 326:119–129PubMedCrossRefGoogle Scholar
  207. Srivastava KD, Rom WJ, Yie TA et al (2002) Crucial role of interleukin-1beta and nitricoxide synthase in silica-induced inflammation and apoptosis in mice. Am J Respir Crit Care Med 165:527–533PubMedCrossRefGoogle Scholar
  208. Steinmetz WE, Rodarte CB, Lin A (2009) 3D QSAR study of the toxicity of trichothecene mycotoxins. Eur J Med Chem 44(11):4485–4489PubMedCrossRefGoogle Scholar
  209. Stephanou A, Latchman DS (2005) Opposing actions of STAT-1 and STAT-3. Growth Factors 23:177–182PubMedCrossRefGoogle Scholar
  210. Su J, Zhao P, Kong L et al (2013) Trichothecin induces cell death in NF-κB constitutively activated human cancer cells via inhibition of IKK phosphorylation. PLoS One 8(8):e71333PubMedCentralPubMedCrossRefGoogle Scholar
  211. Sugita-Konishi Y, Hara-Kudo Y, Kasuga F et al (1988) The effects of trichothecenes on host defense against infectious diseases. Mycotoxins 47:19–23Google Scholar
  212. Sugiyama K, Muroi M, Tanamoto K et al (2010) Deoxynivalenol and nivalenol inhibit lipopolysaccharide-induced nitric oxide production by mouse macrophage cells. Toxicol Lett 192(2):150–154PubMedCrossRefGoogle Scholar
  213. Sugiyama K, Muroi M, Kinoshita M et al (2016) NF-κB activation via MyD88-dependent Toll-like receptor signaling is inhibited by trichothecene mycotoxin deoxynivalenol. J Toxicol Sci 41(2):273–279PubMedCrossRefGoogle Scholar
  214. Tai JH, Pestka JJ (1988) Impaired murine resistance to Salmonella typhimurium following oral exposure to the trichothecene T-2 toxin. Food Chem Toxicol 26(8):691–698PubMedCrossRefGoogle Scholar
  215. Tai JH, Pestka JJ (1990) T-2 toxin impairment of murine response to Salmonella typhimurium: a histopathologic assessment. Mycopathologia 109(3):149–155PubMedCrossRefGoogle Scholar
  216. Tang Y, Li J, Li F et al (2015) Autophagy protects intestinal epithelial cells against deoxynivalenol toxicity by alleviating oxidative stress via IKK signaling pathway. Free Radical Bio Med 89:944–951CrossRefGoogle Scholar
  217. Thomson BJ (2001) Viruses and apoptosis. Int J Exp Pathol 82:65–76PubMedCentralPubMedCrossRefGoogle Scholar
  218. Tian J, Yan J, Wang W et al (2012) T-2 toxin enhances catabolic activity of hypertrophic chondrocytes through ROS-NF-κB-HIF-2α pathway. Toxicol in Vitro 26(7):1106–1113PubMedCrossRefGoogle Scholar
  219. Tien JC, Xu J (2012) Steroid receptor coactivator-3 as a potential molecular target for cancer therapy. Expert Opin Ther Targets 16(11):1085–1096PubMedCentralPubMedCrossRefGoogle Scholar
  220. Tominaga M, Momonaka Y, Yokose C et al (2016) Anorexic action of deoxynivalenol in hypothalamus and intestine. Toxicon 118:54–60Google Scholar
  221. Turkmen K (2017) Inflammation, oxidative stress, apoptosis, and autophagy in diabetes mellitus and diabetic kidney disease: the four Horsemen of the apocalypse. Int Urol Nephrol 49(5):837–844PubMedCrossRefGoogle Scholar
  222. Ueno Y (1985) The toxicology of mycotoxins. Crit Rev Toxicol 14:99–132PubMedCrossRefGoogle Scholar
  223. Uzarski RL, Islam Z, Pestka JJ (2003) Potentiation of trichotheceneinduced leukocyte cytotoxicity and apoptosis by TNF-α and Fas activation. Chem Biol Interact 146:105–119PubMedCrossRefGoogle Scholar
  224. Van De Walle J, Romier B, Larondelle Y et al (2008) Influence of deoxynivalenol on NF-κB activation and IL-8 secretion in human intestinal Caco-2 cells. Toxicol Lett 177(3):205–214PubMedCrossRefGoogle Scholar
  225. Vandenbroucke V, Croubels S, Verbrugghe E et al (2009) The mycotoxin deoxynivalenol promotes uptake of Salmonella typhimurium in porcine macrophages, associated with ERK1/2 induced cytoskeleton reorganization. Vet Res 40(6):64PubMedCrossRefGoogle Scholar
  226. Vandenbroucke V, Croubels S, Martel A et al (2011) The mycotoxin deoxynivalenol potentiates intestinal inflammation by Salmonella typhimurium in porcine ileal loops. PLoS One 6(8):e23871PubMedCentralPubMedCrossRefGoogle Scholar
  227. Verbrugghe E, Croubels S, Vandenbroucke V et al (2011) T-2 toxin alters host-pathogen interactions of Salmonella Typhimurium in pigs. In: 33rd Mycotoxin WorkshopGoogle Scholar
  228. Verbrugghe E, Croubels S, Vandenbroucke V, Goossens J et al (2012a) A modified glucomannan mycotoxin-adsorbing agent counteracts the reduced weight gain and diminishes cecal colonization of Salmonella Typhimurium in T-2 toxin exposed pigs. Res Vet Sci 93(3):1139–1141PubMedCrossRefGoogle Scholar
  229. Verbrugghe E, Vandenbroucke V, Dhaenens M et al (2012b) T-2 toxin induced Salmonella typhimurium intoxication results in decreased Salmonella numbers in the cecum contents of pigs, despite marked effects on Salmonella-host cell interactio. Vet Res 43:22PubMedCentralPubMedCrossRefGoogle Scholar
  230. Vidal D, Mavet S (1989) In vitro and in vivo toxicity of T-2 toxin, a Fusarium mycotoxin, to mouse peritoneal macrophages. Infect Immun 57(7):2260–2264PubMedCentralPubMedGoogle Scholar
  231. Vu HL, Kwon B, Yoon KJ et al (2011) Immune evasion of porcine reproductive and respiratory syndrome virus through glycan shielding involves both glycoprotein 5 as well as glycoprotein 3. J Virol 85(11):5555–5564PubMedCentralPubMedCrossRefGoogle Scholar
  232. Wan D, Wang X, Wu Q et al (2015) Integrated transcriptional and proteomic analysis of growth hormone suppression mediated by trichothecene T-2 toxin in rat GH3 cells. Toxicol Sci 147(2):326–338PubMedCrossRefGoogle Scholar
  233. Wang X, Liu Q, Ihsan A et al (2012) JAK/STAT pathway plays a critical role in the proinflammatory gene expression and apoptosis of RAW264.7 cells induced by trichothecenes as DON and T-2 toxin. Toxicol Sci 127(2):412–424PubMedCrossRefGoogle Scholar
  234. Wang Z, Wu Q, Kuča K et al (2014) Deoxynivalenol: signaling pathways and human exposure risk assessment—an update. Arch Toxicol 88(11):1915–1928PubMedCrossRefGoogle Scholar
  235. Wang YX, Liu YN, Liu XF et al (2015) Citreoviridin induces autophagy-dependent apoptosis through lysosomal-mitochondrial axis in human liver HepG2 cells. Toxins 7(8):3030–3044PubMedCentralPubMedCrossRefGoogle Scholar
  236. Wang X, Wang Y, Qiu M et al (2017) Cytotoxicity of T-2 and modified T-2 toxins: induction of JAK/STAT pathway in RAW264. 7 cells by hepatopancreas and muscle extracts of shrimp fed T-2 toxin. Toxicol Res 6:144–151CrossRefGoogle Scholar
  237. Wannenmacher RW, Wiener SL (1997) Trichothecene mycotoxins. In: Sidell FR, Takafuji ET, Franz DR (eds) Medical aspects of chemical and biological warfare. Office of the Surgeon General at TMM Publications, Washington, DC, USA, pp 655–676Google Scholar
  238. Wei CM, McLaughlin CS (1974) Structure-function relationship in the 12, 13-expoxytrichothecenes-Novel inhibitors of protein synthesis. Biochem Bioph Res Co 57(3):838–844CrossRefGoogle Scholar
  239. Wei S, van der Lee T, Verstappen E et al (2017) Targeting trichothecene biosynthetic genes. Methods Mol Biol 1542:173–189PubMedCrossRefGoogle Scholar
  240. Weidle UH, Tiefenthaler G, Schiller C et al (2014) Prospects of bacterial and plant protein-based immunotoxins for treatment of cancer. Cancer Genom Proteom 11(1):25–38Google Scholar
  241. Wildenberg ME, Koelink PJ, Diederen K et al (2017) The ATG16L1 risk allele associated with Crohn’s disease results in a Rac1-dependent defect in dendritic cell migration that is corrected by thiopurines. Mucosal immunol 10(2):352–360PubMedCrossRefGoogle Scholar
  242. Woldemichael GM, Turbyville TJ, Vasselli JR et al (2012) Lack of a functional VHL gene product sensitizes renal cell carcinoma cells to the apoptotic effects of the protein synthesis inhibitor verrucarin A. Neoplasia 14(8):771–777Google Scholar
  243. Won SJ, Yen CH, Liu HS et al (2015) Justicidin A-induced autophagy flux enhances apoptosis of human colorectal cancer cells via class III PI3K and Atg5 pathway. J Cell Physiol 230(4):930–946Google Scholar
  244. Wu AM, Senter PD (2005) Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol 23(9):1137–1146PubMedCrossRefGoogle Scholar
  245. Wu X, Kohut M, Cunnick J et al (2009) Deoxynivalenol suppresses circulating and splenic leukocyte subpopulations in BALB/c mice: dose response, time course and sex differences. Food Addit Contam A 26(7):1070–1080CrossRefGoogle Scholar
  246. Wu Q, Vlastimil D, Huang L et al (2010) Metabolic pathways of trichothecenes. Drug Metab Rev 42(2):250–267PubMedCrossRefGoogle Scholar
  247. Wu Q, Huang L, Liu Z et al (2011) A comparison of hepatic in vitro metabolism of T-2 toxin in rats, pigs, chickens, and carp. Xenobiotica 41(10):863–873PubMedCrossRefGoogle Scholar
  248. Wu Q, Dohnal V, Kuca K et al (2013) Trichothecenes: structure-toxic activity relationships. Curr Drug Metab 14:641–660PubMedCrossRefGoogle Scholar
  249. Wu QH, Wang X, Yang W et al (2014a) Oxidative stress-mediated cytotoxicity and metabolism of T-2 toxin and deoxynivalenol in animals and humans: an update. Arch Toxicol 88(7):1309–1326PubMedCrossRefGoogle Scholar
  250. Wu Q, Wang X, Wan D et al (2014b) Crosstalk of JNK1-STAT3 is critical for RAW264.7 cell survival. Cell Signal 26:2951–2960PubMedCrossRefGoogle Scholar
  251. Wu J, Tu D, Yuan LY et al (2015) T-2 toxin regulates steroid hormone secretion of rat ovarian granulosa cells through cAMP-PKA pathway. Toxicol Lett 232:573–579PubMedCrossRefGoogle Scholar
  252. Wu W, Zhou HR, Pestka JJ (2017) Potential roles for calcium-sensing receptor (CaSR) and transient receptor potential ankyrin-1 (TRPA1) in murine anorectic response to deoxynivalenol (vomitoxin). Arch Toxicol 91(1):495–507PubMedCrossRefGoogle Scholar
  253. Xu J, Jiang C, Zhu W et al (2015) NOD2 pathway via RIPK2 and TBK1 is involved in the aberrant catabolism induced by T-2 toxin in chondrocytes. Osteoarthr Cartil 23(9):1575–1585PubMedCrossRefGoogle Scholar
  254. Yan F, Yu Y, Chow DC et al (2014) Identification of verrucarin a as a potent and selective steroid receptor coactivator-3 small molecule inhibitor. PLoS One 9(4):e95243PubMedCentralPubMedCrossRefGoogle Scholar
  255. Yang GH, Jarvis BB, Chung YJ et al (2000) Apoptosis induction by the satratoxins and other trichothecene mycotoxins: relationship to ERK, p38 MAPK, and SAPK/JNK activation. Toxicol Appl Pharmacol 164(2):149–160PubMedCrossRefGoogle Scholar
  256. Yang L, Meng HZ, Yang M (2016) Autophagy protects osteoblasts from AGEs induced apoptosis through intracellular ROS. J Mol Endocrinol 56(4):291–300PubMedCrossRefGoogle Scholar
  257. Yin S, Guo X, Li J et al (2016) Fumonisin B1 induces autophagic cell death via activation of ERN1‑MAPK8/9/10 pathway in monkey kidney MARC‑145 cells. Arch Toxicol 90:985–996PubMedCrossRefGoogle Scholar
  258. Ying H, Willingham MC, Cheng SY (2008) The steroid receptor coactivator-3 is a tumor promoter in a mouse model of thyroid cancer. Oncogene 27(6):823–830PubMedCrossRefGoogle Scholar
  259. York B, O’Malley BW (2010) Steroid receptor coactivator (SRC) family: masters of systems biology. J Biol Chem 285(50):38743–38750PubMedCentralPubMedCrossRefGoogle Scholar
  260. Zhang L, Fang B (2005) Mechanisms of resistance to TRAIL-induced apoptosis in cancer. Cancer Gene Ther 12:228–237PubMedCrossRefGoogle Scholar
  261. Zhang Q, Yoo D (2016) Immune evasion of porcine enteric coronaviruses and viral modulation of antiviral innate signaling. Virus Res 226:128–141PubMedCrossRefGoogle Scholar
  262. Zhang Y, Zhang B (2008) TRAIL resistance of breast cancer cells is associated with constitutive endocytosis of death receptors 4 and 5. Mol Cancer Res 6:1861–1871PubMedCrossRefGoogle Scholar
  263. Zhang J, Yang PL, Gray NS (2009) Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9(1):28–39PubMedCrossRefGoogle Scholar
  264. Zhang Y, Han J, Zhu CC et al (2016a) Exposure to HT-2 toxin causes oxidative stress induced apoptosis/autophagy in porcine oocytes. Sci Rep 6:33904PubMedCentralPubMedCrossRefGoogle Scholar
  265. Zhang ZQ, Wang SB, Wang RG et al (2016b) Phosphoproteome analysis reveals the molecular mechanisms underlying deoxynivalenol-induced intestinal toxicity in IPEC-J2 cells. Toxins 8(10):270PubMedCentralCrossRefGoogle Scholar
  266. Zhou HR, Islam Z, Pestka JJ (2003a) Rapid, sequential activation of mitogen-activated protein kinases and transcription factors precedes proinflammatory cytokine mRNA expression in spleens of mice exposed to the trichothecene vomitoxin. Toxicol Sci 72(1):130–142PubMedCrossRefGoogle Scholar
  267. Zhou HR, Lau AS, Pestka JJ (2003b) Role of double-stranded RNA-activated protein kinase R (PKR) in deoxynivalenol-induced ribotoxic stress response. Toxicol Sci 74:335–344PubMedCrossRefGoogle Scholar
  268. Zhou HR, Islam Z, Pestka JJ (2005a) Induction of competing apoptotic and survival signaling pathways in the macrophage by the ribotoixc trichothecene deoxynivalenol. Toxicol Sci 87(1):113–122PubMedCrossRefGoogle Scholar
  269. Zhou HR, Jia Q, Pestka JJ (2005b) Ribotoxic stress response to the trichothecene deoxynivalenol in the macrophage involves the SRC family kinase Hck. Toxicol Sci 85:916–926PubMedCrossRefGoogle Scholar
  270. Zhou HR, He K, Landgraf J et al (2014) Direct activation of ribosome-associated double-stranded RNA-dependent protein kinase (PKR) by deoxynivalenol, anisomycin and ricin: a new model for ribotoxic stress response induction. Toxins 6:3406–3425PubMedCentralPubMedCrossRefGoogle Scholar
  271. Ziprin RL, Elissalde MH (1990) Effect of T-2 toxin on resistance to systemic Salmonella typhimurium infection of newly hatched chickens. Am J Vet Res 51(11):1869–1872PubMedGoogle Scholar
  272. Ziprin RL, McMurray DN (1988) Differential effect of T-2 toxin on murine host resistance to three facultative intracellular bacterial pathogens: listeria monocytogenes, Salmonella typhimurium, and Mycobacterium bovis. Am J Vet Res 49(7):1188–1192PubMedGoogle Scholar
  273. Ziprin RL, Corrier DE, Ziegler HK (1987a) T-2 toxin-enhanced resistance against listeriosis in mice: importance of gastrointestinal lesions. Am J Vet Res 48(6):998–1002PubMedGoogle Scholar
  274. Ziprin RL, Holt PS, Morgensen RF (1987b) T-2 toxin effects on the serum amyloid P-component (SAP) response of Listeria monocytogenes- and Salmonella typhimurium-infected mice. Toxicol Lett 39:177–184PubMedCrossRefGoogle Scholar
  275. Zuk M, Stoehr AM (2002) Immune defense and host life history. Am Nat 160:9–22CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Qinghua Wu
    • 1
    • 2
  • Xu Wang
    • 3
  • Eugenie Nepovimova
    • 2
  • Anca Miron
    • 4
  • Qianying Liu
    • 3
  • Yun Wang
    • 1
  • Dongxiao Su
    • 1
  • Hualin Yang
    • 1
  • Li Li
    • 1
  • Kamil Kuca
    • 2
  1. 1.College of Life Science, Institute of BiomedicineYangtze UniversityJingzhouChina
  2. 2.Department of Chemistry, Faculty of ScienceUniversity of Hradec KraloveHradec KraloveCzech Republic
  3. 3.National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug ResiduesHuazhong Agricultural UniversityWuhanChina
  4. 4.Department of Pharmacognosy, Faculty of PharmacyUniversity of Medicine and Pharmacy Grigore T. PopaIasiRomania

Personalised recommendations