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NF-κB in cellular radiation responses & radiation countermeasures

DISCOVERIES (ISSN 2359-7232), 2015, January-March issue


Singh V, Gupta D, Arora R. NF-κB as a key player in regulation of cellular radiation responses and identification of radiation countermeasures. Discoveries 2015, Jan-Mar; 3(1): e35. DOI: 10.15190/d.2015.27

 Submitted: January 15, 2015; RevisedMarch 17, 2015AcceptedMarch 19, 2015Published: March 31, 2015;


NF-κB as a key player in regulation of cellular radiation responses and identification of radiation countermeasures

Vijay Singh, Damodar Gupta (*), Rajesh Arora

Division  of  Radiation  Biosciences,  Institute  of  Nuclear  Medicine  &  Allied  Sciences,  Brig  SK  Mazumdar Marg, Timarpur, Delhi, India.

*Correspondence to: Damodar Gupta, PhD, Division of Radiation Biosciences, Institute of Nuclear Medicine & Allied Sciences, Defence Research and Development Organisation, Brig. SK Mazumdar Marg, Timarpur, Delhi 110054, India; Phone: 011-23905370; Fax: 011-22919509; Email: damodar@inmas.drdo.in


Nuclear factor (NF)-κB is a transcription factor that plays significant role in immunity,  cellular survival and inhibition of apoptosis, through the induction of genetic networks. Depending on the stimulus and the cell type, the members of NF-κB related family (RelA, c-Rel, RelB, p50, and p52), forms different combinations of homo and hetero-dimers. The activated complexes (Es) translocate into the nucleus and bind to the 10bp κB site of promoter region of target genes in stimulus specific manner. In response to radiation, NF-κB is known to reduce cell death by promoting the expression of anti-apoptotic proteins and activation of cellular antioxidant defense system. Constitutive activation of NF-κB associated genes in tumour cells are known to enhance radiation resistance, whereas deletion in mice results in hypersensitivity to IR-induced GI damage. NF-κB is also known to regulate the production of a wide variety of cytokines and chemokines, which contribute in enhancing cell proliferation and tissue regeneration in various organs, such as the GI crypts stem cells, bone marrow etc., following exposure to IR. Several other cytokines are also known to exert potent pro-inflammatory effects that may contribute to the increase of tissue damage following exposure to ionizing radiation. Till date there are a series of molecules or group of compounds that have been evaluated for their radio-protective potential, and very few have reached clinical trials. The failure or less success of identified agents in humans could be due to their reduced radiation protection efficacy. 

In this review we have considered activation of NF-κB as a potential marker in screening of radiation countermeasure agents (RCAs) and cellular radiation responses. Moreover, we have also focused on associated mechanisms of activation of NF-κB signaling and their specified family member activation with respect to stimuli. Furthermore, we have categorized their regulated gene expressions and their function in radiation response or modulation. In addition, we have discussed some recently developed radiation countermeasures in relation to NF-κB activation.

Access full text of the manuscript here:   Supplementary Material (pdf)


1. Hall EJ, Giaccia AJ. Radiobiology for the Radiologist. Lippincott Williams & Wilkins, 2006.

2. Park WY, Hwang CI, Im CN, Kang MJ, Woo JH, Kim JH, et al. Identification of radiation-specific responses from gene expression profile. Oncogene 2002, 21(55): 8521-8528.

3. Dent P, Yacoub A, Contessa J, Caron R, Amorino G, Valerie K, et al. Stress and radiation-induced activation of multiple intracellular signaling pathways. Radiat Res 2003, 159(3): 283-300.

4. Chaudhry MA. Analysis of gene expression in normal and cancer cells exposed to gamma-radiation. J Biomed Biotechnol 2008, 2008: 541678.

5. Chaudhry MA. Biomarkers for human radiation exposure. J Biomed Sci 2008, 15(5): 557-563.

6. Sen R, Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism. Cell 1986, 47(6): 921-928.

7. Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 1994, 12: 141-179.

8. Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997, 336(15): 1066-1071.

9. Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2002, 2(4): 301-310.

10. Bours V, Bonizzi G, Bentires-Alj M, Bureau F, Piette J, Lekeux P, et al. NF-kappaB activation in response to toxical and therapeutical agents: role in inflammation and cancer treatment. Toxicology 2000, 153(1-3): 27-38.

11. Gancz D, Lusthaus M, Fishelson Z. A role for the NF-kappaB pathway in cell protection from complement-dependent cytotoxicity. J Immunol 2012, 189(2): 860-866.

12. Perkins ND, Gilmore TD. Good cop, bad cop: the different faces of NF-kappaB. Cell Death Differ 2006, 13(5): 759-772.

13. Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene 1999, 18(49): 6853-6866.

14. Silverman N, Maniatis T. NF-kappaB signaling pathways in mammalian and insect innate immunity. Genes Dev 2001, 15(18): 2321-2342.

15. Byrd-Leifer CA, Block EF, Takeda K, Akira S, Ding A. The role of MyD88 and TLR4 in the LPS-mimetic activity of Taxol. Eur J Immunol 2001, 31(8): 2448-2457.

16. Bender K, Gottlicher M, Whiteside S, Rahmsdorf HJ, Herrlich P. Sequential DNA damage-independent and -dependent activation of NF-kappaB by UV. EMBO J 1998, 17(17): 5170-5181.

17. Huang TT, Wuerzberger-Davis SM, Wu ZH, Miyamoto S. Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress. Cell 2003, 115(5): 565-576.

18. Baldwin AS, Jr. Series introduction: the transcription factor NF-kappaB and human disease. J Clin Invest 2001, 107(1): 3-6.

19. Shishodia S, Aggarwal BB. Nuclear factor-kappaB: a friend or a foe in cancer? Biochem Pharmacol 2004, 68(6): 1071-1080.

20. Li Q, Verma IM. NF-kappaB regulation in the immune system. Nat Rev Immunol 2002, 2(10): 725-734.

21. Ahmed KM, Li JJ. NF-kappa B-mediated adaptive resistance to ionizing radiation. Free Radic Biol Med 2008, 44(1): 1-13.

22. Shih VF, Tsui R, Caldwell A, Hoffmann A. A single NFkappaB system for both canonical and non-canonical signaling. Cell Res 2011, 21(1): 86-102.

23. Schmitz ML, Baeuerle PA. The p65 subunit is responsible for the strong transcription activating potential of NF-kappa B. EMBO J 1991, 10(12): 3805-3817.

24. Kuriyan J, Thanos D. Structure of the NF-kappa B transcription factor: a holistic interaction with DNA. Structure 1995, 3(2): 135-141.

25. Ghosh G, van Duyne G, Ghosh S, Sigler PB. Structure of NF-kappa B p50 homodimer bound to a kappa B site. Nature 1995, 373(6512): 303-310.

26. Gossen M, Freundlieb S, Bender G, Muller G, Hillen W, Bujard H. Transcriptional activation by tetracyclines in mammalian cells. Science 1995, 268(5218): 1766-1769.

27. Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev 1995, 9(22): 2723-2735.

28. Nabel GJ, Verma IM. Proposed NF-kappa B/I kappa B family nomenclature. Genes Dev 1993, 7(11): 2063.

29. Hayden MS, Ghosh S. Signaling to NF-kappaB. Genes Dev 2004, 18(18): 2195-2224.

30. May MJ, Ghosh S. Rel/NF-kappa B and I kappa B proteins: an overview. Semin Cancer Biol 1997, 8(2): 63-73.

31. Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-kappaB signaling. Cell Res 2011, 21(1): 103-115.

32. Basak S, Kim H, Kearns JD, Tergaonkar V, O'Dea E, Werner SL, et al. A fourth IkappaB protein within the NF-kappaB signaling module. Cell 2007, 128(2): 369-381.

33. Savinova OV, Hoffmann A, Ghosh G. The Nfkb1 and Nfkb2 proteins p105 and p100 function as the core of high-molecular-weight heterogeneous complexes. Mol Cell 2009, 34(5): 591-602.

34. Dejardin E. The alternative NF-kappaB pathway from biochemistry to biology: pitfalls and promises for future drug development. Biochem Pharmacol 2006, 72(9): 1161-1179.

35. Sha WC. Regulation of immune responses by NF-kappa B/Rel transcription factor. J Exp Med 1998, 187(2): 143-146.

36. Delhase M, Hayakawa M, Chen Y, Karin M. Positive and negative regulation of IkappaB kinase activity through IKKbeta subunit phosphorylation. Science 1999, 284(5412): 309-313.

37. Li ZW, Chu W, Hu Y, Delhase M, Deerinck T, Ellisman M, et al. The IKKbeta subunit of IkappaB kinase (IKK) is essential for nuclear factor kappaB activation and prevention of apoptosis. J Exp Med 1999, 189(11): 1839-1845.

38. Chen JY, Penco S, Ostrowski J, Balaguer P, Pons M, Starrett JE, et al. RAR-specific agonist/antagonists which dissociate transactivation and AP1 transrepression inhibit anchorage-independent cell proliferation. EMBO J 1995, 14(6): 1187-1197.

39. Baeuerle PA, Rupec RA, Pahl HL. Reactive oxygen intermediates as second messengers of a general pathogen response. Pathol Biol (Paris) 1996, 44(1): 29-35.

40. Bellezza I, Mierla AL, Minelli A. Nrf2 and NF-kappaB and Their Concerted Modulation in Cancer Pathogenesis and Progression. Cancers (Basel) 2010, 2(2): 483-497.

41. Xiao G, Harhaj EW, Sun SC. NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100. Mol Cell 2001, 7(2): 401-409.

42. Liao G, Zhang M, Harhaj EW, Sun SC. Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation. J Biol Chem 2004, 279(25): 26243-26250.

43. Kato T, Jr., Delhase M, Hoffmann A, Karin M. CK2 Is a C-Terminal IkappaB Kinase Responsible for NF-kappaB Activation during the UV Response. Mol Cell 2003, 12(4): 829-839.

44. Tergaonkar V, Bottero V, Ikawa M, Li Q, Verma IM. IkappaB kinase-independent IkappaBalpha degradation pathway: functional NF-kappaB activity and implications for cancer therapy. Mol Cell Biol 2003, 23(22): 8070-8083.

45. Ahmed K, Gerber DA, Cochet C. Joining the cell survival squad: an emerging role for protein kinase CK2. Trends Cell Biol 2002, 12(5): 226-230.

46. Litchfield DW. Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem J 2003, 369(Pt 1): 1-15.

47. Jung M, Zhang Y, Lee S, Dritschilo A. Correction of radiation sensitivity in ataxia telangiectasia cells by a truncated I kappa B-alpha. Science 1995, 268(5217): 1619-1621.

48. Wu ZH, Shi Y, Tibbetts RS, Miyamoto S. Molecular linkage between the kinase ATM and NF-kappaB signaling in response to genotoxic stimuli. Science 2006, 311(5764): 1141-1146.

49. Takada Y, Mukhopadhyay A, Kundu GC, Mahabeleshwar GH, Singh S, Aggarwal BB. Hydrogen peroxide activates NF-kappa B through tyrosine phosphorylation of I kappa B alpha and serine phosphorylation of p65: evidence for the involvement of I kappa B alpha kinase and Syk protein-tyrosine kinase. J Biol Chem 2003, 278(26): 24233-24241.

50. Gloire G, Legrand-Poels S, Piette J. NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 2006, 72(11): 1493-1505.

51. Schmidt KN, Amstad P, Cerutti P, Baeuerle PA. The roles of hydrogen peroxide and superoxide as messengers in the activation of transcription factor NF-kappa B. Chem Biol 1995, 2(1): 13-22.

52. Matthews JR, Wakasugi N, Virelizier JL, Yodoi J, Hay RT. Thioredoxin regulates the DNA binding activity of NF-kappa B by reduction of a disulphide bond involving cysteine 62. Nucleic Acids Res 1992, 20(15): 3821-3830.

53. Matthews JR, Kaszubska W, Turcatti G, Wells TN, Hay RT. Role of cysteine62 in DNA recognition by the P50 subunit of NF-kappa B. Nucleic Acids Res 1993, 21(8): 1727-1734.

54. Droge W, Schulze-Osthoff K, Mihm S, Galter D, Schenk H, Eck HP, et al. Functions of glutathione and glutathione disulfide in immunology and immunopathology. FASEB J 1994, 8(14): 1131-1138.

55. Bowie A, O'Neill LA. Oxidative stress and nuclear factor-kappaB activation: a reassessment of the evidence in the light of recent discoveries. Biochem Pharmacol 2000, 59(1): 13-23.

56. Mukhopadhyay A, Manna SK, Aggarwal BB. Pervanadate-induced nuclear factor-kappaB activation requires tyrosine phosphorylation and degradation of IkappaBalpha. Comparison with tumor necrosis factor-alpha. J Biol Chem 2000, 275(12): 8549-8555.

57. Li N, Karin M. Ionizing radiation and short wavelength UV activate NF-kappaB through two distinct mechanisms. Proc Natl Acad Sci U S A 1998, 95(22): 13012-13017.

58. Natoli G, Saccani S, Bosisio D, Marazzi I. Interactions of NF-kappaB with chromatin: the art of being at the right place at the right time. Nat Immunol 2005, 6(5): 439-445.

59. Hoffmann A, Natoli G, Ghosh G. Transcriptional regulation via the NF-kappaB signaling module. Oncogene 2006, 25(51): 6706-6716.

60. Hayden MS, Ghosh S. Shared principles in NF-kappaB signaling. Cell 2008, 132(3): 344-362.

61. Wietek C, O'Neill LA. Diversity and regulation in the NF-kappaB system. Trends Biochem Sci 2007, 32(7): 311-319.

62. Neumann M, Naumann M. Beyond IkappaBs: alternative regulation of NF-kappaB activity. FASEB J 2007, 21(11): 2642-2654.

63. Perkins ND. Post-translational modifications regulating the activity and function of the nuclear factor kappa B pathway. Oncogene 2006, 25(51): 6717-6730.

64. Viatour P, Merville MP, Bours V, Chariot A. Phosphorylation of NF-kappaB and IkappaB proteins: implications in cancer and inflammation. Trends Biochem Sci 2005, 30(1): 43-52.

65. Chen LF, Greene WC. Shaping the nuclear action of NF-kappaB. Nat Rev Mol Cell Biol 2004, 5(5): 392-401.

66. Anrather J, Racchumi G, Iadecola C. cis-acting, element-specific transcriptional activity of differentially phosphorylated nuclear factor-kappa B. J Biol Chem 2005, 280(1): 244-252.

67. Zhong H, Voll RE, Ghosh S. Phosphorylation of NF-kappa B p65 by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. Mol Cell 1998, 1(5): 661-671.

68. Vermeulen L, De Wilde G, Van Damme P, Vanden Berghe W, Haegeman G. Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J 2003, 22(6): 1313-1324.

69. Duran A, Diaz-Meco MT, Moscat J. Essential role of RelA Ser311 phosphorylation by zetaPKC in NF-kappaB transcriptional activation. EMBO J 2003, 22(15): 3910-3918.

70. Buss H, Dorrie A, Schmitz ML, Frank R, Livingstone M, Resch K, et al. Phosphorylation of serine 468 by GSK-3beta negatively regulates basal p65 NF-kappaB activity. J Biol Chem 2004, 279(48): 49571-49574.

71. Schwabe RF, Sakurai H. IKKbeta phosphorylates p65 at S468 in transactivaton domain 2. FASEB J 2005, 19(12): 1758-1760.

72. Mattioli I, Geng H, Sebald A, Hodel M, Bucher C, Kracht M, et al. Inducible phosphorylation of NF-kappa B p65 at serine 468 by T cell costimulation is mediated by IKK epsilon. J Biol Chem 2006, 281(10): 6175-6183.

73. Wang D, Westerheide SD, Hanson JL, Baldwin AS, Jr. Tumor necrosis factor alpha-induced phosphorylation of RelA/p65 on Ser529 is controlled by casein kinase II. J Biol Chem 2000, 275(42): 32592-32597.

74. Bae JS, Jang MK, Hong S, An WG, Choi YH, Kim HD, et al. Phosphorylation of NF-kappa B by calmodulin-dependent kinase IV activates anti-apoptotic gene expression. Biochem Biophys Res Commun 2003, 305(4): 1094-1098.

75. Jiang X, Takahashi N, Matsui N, Tetsuka T, Okamoto T. The NF-kappa B activation in lymphotoxin beta receptor signaling depends on the phosphorylation of p65 at serine 536. J Biol Chem 2003, 278(2): 919-926.

76. Lawrence T, Bebien M, Liu GY, Nizet V, Karin M. IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation. Nature 2005, 434(7037): 1138-1143.

77. Sakurai H, Chiba H, Miyoshi H, Sugita T, Toriumi W. IkappaB kinases phosphorylate NF-kappaB p65 subunit on serine 536 in the transactivation domain. J Biol Chem 1999, 274(43): 30353-30356.

78. Mattioli I, Sebald A, Bucher C, Charles RP, Nakano H, Doi T, et al. Transient and selective NF-kappa B p65 serine 536 phosphorylation induced by T cell costimulation is mediated by I kappa B kinase beta and controls the kinetics of p65 nuclear import. J Immunol 2004, 172(10): 6336-6344.

79. Buss H, Dorrie A, Schmitz ML, Hoffmann E, Resch K, Kracht M. Constitutive and interleukin-1-inducible phosphorylation of p65 NF-{kappa}B at serine 536 is mediated by multiple protein kinases including I{kappa}B kinase (IKK)-{alpha}, IKK{beta}, IKK{epsilon}, TRAF family member-associated (TANK)-binding kinase 1 (TBK1), and an unknown kinase and couples p65 to TATA-binding protein-associated factor II31-mediated interleukin-8 transcription. J Biol Chem 2004, 279(53): 55633-55643.

80. Fujita F, Taniguchi Y, Kato T, Narita Y, Furuya A, Ogawa T, et al. Identification of NAP1, a regulatory subunit of IkappaB kinase-related kinases that potentiates NF-kappaB signaling. Mol Cell Biol 2003, 23(21): 7780-7793.

81. Bohuslav J, Chen LF, Kwon H, Mu Y, Greene WC. p53 induces NF-kappaB activation by an IkappaB kinase-independent mechanism involving phosphorylation of p65 by ribosomal S6 kinase 1. J Biol Chem 2004, 279(25): 26115-26125.

82. Sabatel H, Di Valentin E, Gloire G, Dequiedt F, Piette J, Habraken Y. Phosphorylation of p65(RelA) on Ser(547) by ATM represses NF-kappaB-dependent transcription of specific genes after genotoxic stress. PLoS One 2012, 7(6): e38246.

83. Ryo A, Suizu F, Yoshida Y, Perrem K, Liou YC, Wulf G, et al. Regulation of NF-kappaB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Mol Cell 2003, 12(6): 1413-1426.

84. Yeh PY, Yeh KH, Chuang SE, Song YC, Cheng AL. Suppression of MEK/ERK signaling pathway enhances cisplatin-induced NF-kappaB activation by protein phosphatase 4-mediated NF-kappaB p65 Thr dephosphorylation. J Biol Chem 2004, 279(25): 26143-26148.

85. Campbell KJ, Witty JM, Rocha S, Perkins ND. Cisplatin mimics ARF tumor suppressor regulation of RelA (p65) nuclear factor-kappaB transactivation. Cancer Res 2006, 66(2): 929-935.

86. Campbell KJ, Perkins ND. Regulation of NF-kappaB function. Biochem Soc Symp 2006(73): 165-180.

87. Park SW, Huq MD, Hu X, Wei LN. Tyrosine nitration on p65: a novel mechanism to rapidly inactivate nuclear factor-kappaB. Mol Cell Proteomics 2005, 4(3): 300-309.

88. Kiernan R, Bres V, Ng RW, Coudart MP, El Messaoudi S, Sardet C, et al. Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65. J Biol Chem 2003, 278(4): 2758-2766.

89. Chen LF, Mu Y, Greene WC. Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kappaB. EMBO J 2002, 21(23): 6539-6548.

90. Buerki C, Rothgiesser KM, Valovka T, Owen HR, Rehrauer H, Fey M, et al. Functional relevance of novel p300-mediated lysine 314 and 315 acetylation of RelA/p65. Nucleic Acids Res 2008, 36(5): 1665-1680.

91. Hoberg JE, Popko AE, Ramsey CS, Mayo MW. IkappaB kinase alpha-mediated derepression of SMRT potentiates acetylation of RelA/p65 by p300. Mol Cell Biol 2006, 26(2): 457-471.

92. Dong J, Jimi E, Zhong H, Hayden MS, Ghosh S. Repression of gene expression by unphosphorylated NF-kappaB p65 through epigenetic mechanisms. Genes Dev 2008, 22(9): 1159-1173.

93. Geng H, Wittwer T, Dittrich-Breiholz O, Kracht M, Schmitz ML. Phosphorylation of NF-kappaB p65 at Ser468 controls its COMMD1-dependent ubiquitination and target gene-specific proteasomal elimination. EMBO Rep 2009, 10(4): 381-386.

94. Nowak DE, Tian B, Jamaluddin M, Boldogh I, Vergara LA, Choudhary S, et al. RelA Ser276 phosphorylation is required for activation of a subset of NF-kappaB-dependent genes by recruiting cyclin-dependent kinase 9/cyclin T1 complexes. Mol Cell Biol 2008, 28(11): 3623-3638.

95. Moreno R, Sobotzik JM, Schultz C, Schmitz ML. Specification of the NF-kappaB transcriptional response by p65 phosphorylation and TNF-induced nuclear translocation of IKK epsilon. Nucleic Acids Res 2010, 38(18): 6029-6044.

96. Heissmeyer V, Krappmann D, Hatada EN, Scheidereit C. Shared pathways of IkappaB kinase-induced SCF(betaTrCP)-mediated ubiquitination and degradation for the NF-kappaB precursor p105 and IkappaBalpha. Mol Cell Biol 2001, 21(4): 1024-1035.

97. Orian A, Gonen H, Bercovich B, Fajerman I, Eytan E, Israel A, et al. SCF(beta)(-TrCP) ubiquitin ligase-mediated processing of NF-kappaB p105 requires phosphorylation of its C-terminus by IkappaB kinase. EMBO J 2000, 19(11): 2580-2591.

98. Wan F, Anderson DE, Barnitz RA, Snow A, Bidere N, Zheng L, et al. Ribosomal protein S3: a KH domain subunit in NF-kappaB complexes that mediates selective gene regulation. Cell 2007, 131(5): 927-939.

99. Kelsey KT, Memisoglu A, Frenkel D, Liber HL. Human lymphocytes exposed to low doses of X-rays are less susceptible to radiation-induced mutagenesis. Mutat Res 1991, 263(4): 197-201.

100. Feinendegen LE, Bond VP, Sondhaus CA, Muehlensiepen H. Radiation effects induced by low doses in complex tissue and their relation to cellular adaptive responses. Mutat Res 1996, 358(2): 199-205.

101. Jones PL, Ping D, Boss JM. Tumor necrosis factor alpha and interleukin-1beta regulate the murine manganese superoxide dismutase gene through a complex intronic enhancer involving C/EBP-beta and NF-kappaB. Mol Cell Biol 1997, 17(12): 6970-6981.

102. Das KC, Lewis-Molock Y, White CW. Activation of NF-kappa B and elevation of MnSOD gene expression by thiol reducing agents in lung adenocarcinoma (A549) cells. Am J Physiol 1995, 269(5 Pt 1): L588-602.

103. Li Y, Huang TT, Carlson EJ, Melov S, Ursell PC, Olson JL, et al. Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet 1995, 11(4): 376-381.

104. Macmillan-Crow LA, Cruthirds DL. Invited review: manganese superoxide dismutase in disease. Free Radic Res 2001, 34(4): 325-336.

105. Elchuri S, Oberley TD, Qi W, Eisenstein RS, Jackson Roberts L, Van Remmen H, et al. CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 2005, 24(3): 367-380.

106. Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, Alvarez K, et al. Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species. Cell 2004, 119(4): 529-542.

107. Torti FM, Torti SV. Regulation of ferritin genes and protein. Blood 2002, 99(10): 3505-3516.

108. Schreiber J, Jenner RG, Murray HL, Gerber GK, Gifford DK, Young RA. Coordinated binding of NF-kappaB family members in the response of human cells to lipopolysaccharide. Proc Natl Acad Sci U S A 2006, 103(15): 5899-5904.

109. Chelikani P, Fita I, Loewen PC. Diversity of structures and properties among catalases. Cell Mol Life Sci 2004, 61(2): 192-208.

110. Djavaheri-Mergny M, Javelaud D, Wietzerbin J, Besancon F. NF-kappaB activation prevents apoptotic oxidative stress via an increase of both thioredoxin and MnSOD levels in TNFalpha-treated Ewing sarcoma cells. FEBS Lett 2004, 578(1-2): 111-115.

111. Matsui M, Oshima M, Oshima H, Takaku K, Maruyama T, Yodoi J, et al. Early embryonic lethality caused by targeted disruption of the mouse thioredoxin gene. Dev Biol 1996, 178(1): 179-185.

112. Tanaka T, Hosoi F, Yamaguchi-Iwai Y, Nakamura H, Masutani H, Ueda S, et al. Thioredoxin-2 (TRX-2) is an essential gene regulating mitochondria-dependent apoptosis. EMBO J 2002, 21(7): 1695-1703.

113. Nonn L, Williams RR, Erickson RP, Powis G. The absence of mitochondrial thioredoxin 2 causes massive apoptosis, exencephaly, and early embryonic lethality in homozygous mice. Mol Cell Biol 2003, 23(3): 916-922.

114. Xia C, Hu J, Ketterer B, Taylor JB. The organization of the human GSTP1-1 gene promoter and its response to retinoic acid and cellular redox status. Biochem J 1996, 313 ( Pt 1): 155-161.

115. Dang DT, Chen F, Kohli M, Rago C, Cummins JM, Dang LH. Glutathione S-transferase pi1 promotes tumorigenicity in HCT116 human colon cancer cells. Cancer Res 2005, 65(20): 9485-9494.

116. Dourado DF, Fernandes PA, Ramos MJ. Mammalian cytosolic glutathione transferases. Curr Protein Pept Sci 2008, 9(4): 325-337.

117. Salinas AE, Wong MG. Glutathione S-transferases--a review. Curr Med Chem 1999, 6(4): 279-309.

118. Hinata K, Gervin AM, Jennifer Zhang Y, Khavari PA. Divergent gene regulation and growth effects by NF-kappa B in epithelial and mesenchymal cells of human skin. Oncogene 2003, 22(13): 1955-1964.

119. Kumari MV, Hiramatsu M, Ebadi M. Free radical scavenging actions of metallothionein isoforms I and II. Free Radic Res 1998, 29(2): 93-101.

120. Howells C, West AK, Chung RS. Neuronal growth-inhibitory factor (metallothionein-3): evaluation of the biological function of growth-inhibitory factor in the injured and neurodegenerative brain. FEBS J 2010, 277(14): 2931-2939.

121. Yao KS, Hageboutros A, Ford P, O'Dwyer PJ. Involvement of activator protein-1 and nuclear factor-kappaB transcription factors in the control of the DT-diaphorase expression induced by mitomycin C treatment. Mol Pharmacol 1997, 51(3): 422-430.

122. Ahn KS, Sethi G, Jain AK, Jaiswal AK, Aggarwal BB. Genetic deletion of NAD(P)H:quinone oxidoreductase 1 abrogates activation of nuclear factor-kappaB, IkappaBalpha kinase, c-Jun N-terminal kinase, Akt, p38, and p44/42 mitogen-activated protein kinases and potentiates apoptosis. J Biol Chem 2006, 281(29): 19798-19808.

123. Dinkova-Kostova AT, Talalay P. NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector. Arch Biochem Biophys 2010, 501(1): 116-123.

124. Wu G, Marin-Garcia J, Rogers TB, Lakatta EG, Long X. Phosphorylation and hypoxia-induced heme oxygenase-1 gene expression in cardiomyocytes. J Card Fail 2004, 10(6): 519-526.

125. Prawan A, Kundu JK, Surh YJ. Molecular basis of heme oxygenase-1 induction: implications for chemoprevention and chemoprotection. Antioxid Redox Signal 2005, 7(11-12): 1688-1703.

126. Lei XG, Cheng WH, McClung JP. Metabolic regulation and function of glutathione peroxidase-1. Annu Rev Nutr 2007, 27: 41-61.

127. Sies H, Sharov VS, Klotz LO, Briviba K. Glutathione peroxidase protects against peroxynitrite-mediated oxidations. A new function for selenoproteins as peroxynitrite reductase. J Biol Chem 1997, 272(44): 27812-27817.

128. Ciaccio PJ, Walsh ES, Tew KD. Promoter analysis of a human dihydrodiol dehydrogenase. Biochem Biophys Res Commun 1996, 228(2): 524-529.

129. Chen J, Adikari M, Pallai R, Parekh HK, Simpkins H. Dihydrodiol dehydrogenases regulate the generation of reactive oxygen species and the development of cisplatin resistance in human ovarian carcinoma cells. Cancer Chemother Pharmacol 2008, 61(6): 979-987.

130. Anrather J, Racchumi G, Iadecola C. NF-kappaB regulates phagocytic NADPH oxidase by inducing the expression of gp91phox. J Biol Chem 2006, 281(9): 5657-5667.

131. Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 2004, 4(3): 181-189.

132. Brown DI, Griendling KK. Nox proteins in signal transduction. Free Radic Biol Med 2009, 47(9): 1239-1253.

133. Xu P, Huecksteadt TP, Hoidal JR. Molecular cloning and characterization of the human xanthine dehydrogenase gene (XDH). Genomics 1996, 34(2): 173-180.

134. Maia L, Vala A, Mira L. NADH oxidase activity of rat liver xanthine dehydrogenase and xanthine oxidase-contribution for damage mechanisms. Free Radic Res 2005, 39(9): 979-986.

135. Kolyada AY, Savikovsky N, Madias NE. Transcriptional regulation of the human iNOS gene in vascular-smooth-muscle cells and macrophages: evidence for tissue specificity. Biochem Biophys Res Commun 1996, 220(3): 600-605.

136. Nakata S, Tsutsui M, Shimokawa H, Yamashita T, Tanimoto A, Tasaki H, et al. Statin treatment upregulates vascular neuronal nitric oxide synthase through Akt/NF-kappaB pathway. Arterioscler Thromb Vasc Biol 2007, 27(1): 92-98.

137. Li Y, Zhao Y, Li G, Wang J, Li T, Li W, et al. Regulation of neuronal nitric oxide synthase exon 1f gene expression by nuclear factor-kappaB acetylation in human neuroblastoma cells. J Neurochem 2007, 101(5): 1194-1204.

138. Morris KR, Lutz RD, Choi HS, Kamitani T, Chmura K, Chan ED. Role of the NF-kappaB signaling pathway and kappaB cis-regulatory elements on the IRF-1 and iNOS promoter regions in mycobacterial lipoarabinomannan induction of nitric oxide. Infect Immun 2003, 71(3): 1442-1452.

139. Ahmad R, Rasheed Z, Ahsan H. Biochemical and cellular toxicology of peroxynitrite: implications in cell death and autoimmune phenomenon. Immunopharmacol Immunotoxicol 2009, 31(3): 388-396.

140. Marnett LJ, Rowlinson SW, Goodwin DC, Kalgutkar AS, Lanzo CA. Arachidonic acid oxygenation by COX-1 and COX-2. Mechanisms of catalysis and inhibition. J Biol Chem 1999, 274(33): 22903-22906.

141. Arakawa T, Nakamura M, Yoshimoto T, Yamamoto S. The transcriptional regulation of human arachidonate 12-lipoxygenase gene by NF kappa B/Rel. FEBS Lett 1995, 363(1-2): 105-110.

142. Chopra A, Ferreira-Alves DL, Sirois P, Thirion JP. Cloning of the guinea pig 5-lipoxygenase gene and nucleotide sequence of its promoter. Biochem Biophys Res Commun 1992, 185(2): 489-495.

143. Kim C, Kim JY, Kim JH. Cytosolic phospholipase A(2), lipoxygenase metabolites, and reactive oxygen species. BMB Rep 2008, 41(8): 555-559.

144. Nordblom GD, Coon MJ. Hydrogen peroxide formation and stoichiometry of hydroxylation reactions catalyzed by highly purified liver microsomal cytochrome P-450. Arch Biochem Biophys 1977, 180(2): 343-347.

145. Imaoka S, Osada M, Minamiyama Y, Yukimura T, Toyokuni S, Takemura S, et al. Role of phenobarbital-inducible cytochrome P450s as a source of active oxygen species in DNA-oxidation. Cancer Lett 2004, 203(2): 117-125.

146. Abdel-Razzak Z, Garlatti M, Aggerbeck M, Barouki R (eds). Determination of interleukin-4-responsive region in the human cytochrome P450 2E1 gene promoter, 2004.

147. Morgan ET, Li-Masters T, Cheng PY. Mechanisms of cytochrome P450 regulation by inflammatory mediators. Toxicology 2002, 181-182: 207-210.

148. Caro AA, Cederbaum AI. Oxidative stress, toxicology, and pharmacology of CYP2E1. Annu Rev Pharmacol Toxicol 2004, 44: 27-42.

149. Cederbaum AI, Wu D, Mari M, Bai J. CYP2E1-dependent toxicity and oxidative stress in HepG2 cells. Free Radic Biol Med 2001, 31(12): 1539-1543.

150. Deveraux QL, Reed JC. IAP family proteins--suppressors of apoptosis. Genes Dev 1999, 13(3): 239-252.

151. Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, et al. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J 1998, 17(8): 2215-2223.

152. Kasof GM, Gomes BC. Livin, a novel inhibitor of apoptosis protein family member. J Biol Chem 2001, 276(5): 3238-3246.

153. Deveraux QL, Takahashi R, Salvesen GS, Reed JC. X-linked IAP is a direct inhibitor of cell-death proteases. Nature 1997, 388(6639): 300-304.

154. Tang G, Minemoto Y, Dibling B, Purcell NH, Li Z, Karin M, et al. Inhibition of JNK activation through NF-kappaB target genes. Nature 2001, 414(6861): 313-317.

155. Benayoun B, Baghdiguian S, Lajmanovich A, Bartoli M, Daniele N, Gicquel E, et al. NF-kappaB-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3, the protein involved in limb-girdle muscular dystrophy type 2A. FASEB J 2008, 22(5): 1521-1529.

156. Golks A, Brenner D, Krammer PH, Lavrik IN. The c-FLIP-NH2 terminus (p22-FLIP) induces NF-kappaB activation. J Exp Med 2006, 203(5): 1295-1305.

157. Iyer AK, Azad N, Talbot S, Stehlik C, Lu B, Wang L, et al. Antioxidant c-FLIP inhibits Fas ligand-induced NF-kappaB activation in a phosphatidylinositol 3-kinase/Akt-dependent manner. J Immunol 2011, 187(6): 3256-3266.

158. Catz SD, Johnson JL. Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. Oncogene 2001, 20(50): 7342-7351.

159. Buchholz TA, Garg AK, Chakravarti N, Aggarwal BB, Esteva FJ, Kuerer HM, et al. The nuclear transcription factor kappaB/bcl-2 pathway correlates with pathologic complete response to doxorubicin-based neoadjuvant chemotherapy in human breast cancer. Clin Cancer Res 2005, 11(23): 8398-8402.

160. Murphy KM, Ranganathan V, Farnsworth ML, Kavallaris M, Lock RB. Bcl-2 inhibits Bax translocation from cytosol to mitochondria during drug-induced apoptosis of human tumor cells. Cell Death Differ 2000, 7(1): 102-111.

161. Zhu L, Ling S, Yu XD, Venkatesh LK, Subramanian T, Chinnadurai G, et al. Modulation of mitochondrial Ca(2+) homeostasis by Bcl-2. J Biol Chem 1999, 274(47): 33267-33273.

162. Deng X, Xiao L, Lang W, Gao F, Ruvolo P, May WS, Jr. Novel role for JNK as a stress-activated Bcl2 kinase. J Biol Chem 2001, 276(26): 23681-23688.

163. Chen C, Edelstein LC, Gelinas C. The Rel/NF-kappaB family directly activates expression of the apoptosis inhibitor Bcl-x(L). Mol Cell Biol 2000, 20(8): 2687-2695.

164. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998, 281(5381): 1322-1326.

165. Minn AJ, Kettlun CS, Liang H, Kelekar A, Vander Heiden MG, Chang BS, et al. Bcl-xL regulates apoptosis by heterodimerization-dependent and -independent mechanisms. EMBO J 1999, 18(3): 632-643.

166. Vander Heiden MG, Li XX, Gottleib E, Hill RB, Thompson CB, Colombini M. Bcl-xL promotes the open configuration of the voltage-dependent anion channel and metabolite passage through the outer mitochondrial membrane. J Biol Chem 2001, 276(22): 19414-19419.

167. Fan M, Goodwin M, Vu T, Brantley-Finley C, Gaarde WA, Chambers TC. Vinblastine-induced phosphorylation of Bcl-2 and Bcl-XL is mediated by JNK and occurs in parallel with inactivation of the Raf-1/MEK/ERK cascade. J Biol Chem 2000, 275(39): 29980-29985.

168. Poruchynsky MS, Wang EE, Rudin CM, Blagosklonny MV, Fojo T. Bcl-xL is phosphorylated in malignant cells following microtubule disruption. Cancer Res 1998, 58(15): 3331-3338.

169. Jung M, Dritschilo A. NF-kappa B signaling pathway as a target for human tumor radiosensitization. Semin Radiat Oncol 2001, 11(4): 346-351.

170. Zhou D, Brown SA, Yu T, Chen G, Barve S, Kang BC, et al. A high dose of ionizing radiation induces tissue-specific activation of nuclear factor-kappaB in vivo. Radiat Res 1999, 151(6): 703-709.

171. Guttridge DC, Albanese C, Reuther JY, Pestell RG, Baldwin AS, Jr. NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol Cell Biol 1999, 19(8): 5785-5799.

172. Hirai H, Roussel MF, Kato JY, Ashmun RA, Sherr CJ. Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Mol Cell Biol 1995, 15(5): 2672-2681.

173. Sherr CJ. Cancer cell cycles. Science 1996, 274(5293): 1672-1677.

174. Lukas J, Bartkova J, Bartek J. Convergence of mitogenic signalling cascades from diverse classes of receptors at the cyclin D-cyclin-dependent kinase-pRb-controlled G1 checkpoint. Mol Cell Biol 1996, 16(12): 6917-6925.

175. Diehl JA, Zindy F, Sherr CJ. Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Genes Dev 1997, 11(8): 957-972.

176. Fan M, Ahmed KM, Coleman MC, Spitz DR, Li JJ. Nuclear factor-kappaB and manganese superoxide dismutase mediate adaptive radioresistance in low-dose irradiated mouse skin epithelial cells. Cancer Res 2007, 67(7): 3220-3228.

177. Lorca T, Labbe JC, Devault A, Fesquet D, Capony JP, Cavadore JC, et al. Dephosphorylation of cdc2 on threonine 161 is required for cdc2 kinase inactivation and normal anaphase. EMBO J 1992, 11(7): 2381-2390.

178. Norbury C, Blow J, Nurse P. Regulatory phosphorylation of the p34cdc2 protein kinase in vertebrates. EMBO J 1991, 10(11): 3321-3329.

179. Toyoshima-Morimoto F, Taniguchi E, Shinya N, Iwamatsu A, Nishida E. Polo-like kinase 1 phosphorylates cyclin B1 and targets it to the nucleus during prophase. Nature 2001, 410(6825): 215-220.

180. Papa S, Zazzeroni F, Bubici C, Jayawardena S, Alvarez K, Matsuda S, et al. Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2. Nat Cell Biol 2004, 6(2): 146-153.

181. Wang T, Hu YC, Dong S, Fan M, Tamae D, Ozeki M, et al. Co-activation of ERK, NF-kappaB, and GADD45beta in response to ionizing radiation. J Biol Chem 2005, 280(13): 12593-12601.

182. Wang XW, Zhan Q, Coursen JD, Khan MA, Kontny HU, Yu L, et al. GADD45 induction of a G2/M cell cycle checkpoint. Proc Natl Acad Sci U S A 1999, 96(7): 3706-3711.

183. Yang Q, Manicone A, Coursen JD, Linke SP, Nagashima M, Forgues M, et al. Identification of a functional domain in a GADD45-mediated G2/M checkpoint. J Biol Chem 2000, 275(47): 36892-36898.

184. Zhao H, Jin S, Antinore MJ, Lung FD, Fan F, Blanck P, et al. The central region of Gadd45 is required for its interaction with p21/WAF1. Exp Cell Res 2000, 258(1): 92-100.

185. Liebermann DA, Hoffman B. Gadd45 in stress signaling. J Mol Signal 2008, 3: 15.

186. Lim JW, Kim H, Kim KH. Expression of Ku70 and Ku80 mediated by NF-kappa B and cyclooxygenase-2 is related to proliferation of human gastric cancer cells. J Biol Chem 2002, 277(48): 46093-46100.

187. Tuteja R, Tuteja N. Ku autoantigen: a multifunctional DNA-binding protein. Crit Rev Biochem Mol Biol 2000, 35(1): 1-33.

188. Cao QP, Pitt S, Leszyk J, Baril EF. DNA-dependent ATPase from HeLa cells is related to human Ku autoantigen. Biochemistry 1994, 33(28): 8548-8557.

189. Collis SJ, DeWeese TL, Jeggo PA, Parker AR. The life and death of DNA-PK. Oncogene 2005, 24(6): 949-961.

190. Cao N, Li S, Wang Z, Ahmed KM, Degnan ME, Fan M, et al. NF-kappaB-mediated HER2 overexpression in radiation-adaptive resistance. Radiat Res 2009, 171(1): 9-21.

191. Muthuswamy SK, Gilman M, Brugge JS. Controlled dimerization of ErbB receptors provides evidence for differential signaling by homo- and heterodimers. Mol Cell Biol 1999, 19(10): 6845-6857.

192. Rosen EM, Day R, Singh VK. New approaches to radiation protection. Front Oncol 2014, 4: 381.

193. Citrin D, Cotrim AP, Hyodo F, Baum BJ, Krishna MC, Mitchell JB. Radioprotectors and mitigators of radiation-induced normal tissue injury. Oncologist 2010, 15(4): 360-371.

194. Gudkov AV, Komarova EA. The role of p53 in determining sensitivity to radiotherapy. Nat Rev Cancer 2003, 3(2): 117-129.

195. Potten CS. The significance of spontaneous and induced apoptosis in the gastrointestinal tract of mice. Cancer Metastasis Rev 1992, 11(2): 179-195.

196. Kolesnick R, Fuks Z. Radiation and ceramide-induced apoptosis. Oncogene 2003, 22(37): 5897-5906.

197. Wang Y, Meng A, Lang H, Brown SA, Konopa JL, Kindy MS, et al. Activation of nuclear factor kappaB In vivo selectively protects the murine small intestine against ionizing radiation-induced damage. Cancer Res 2004, 64(17): 6240-6246.

198. Stone HB, Moulder JE, Coleman CN, Ang KK, Anscher MS, Barcellos-Hoff MH, et al. Models for evaluating agents intended for the prophylaxis, mitigation and treatment of radiation injuries. Report of an NCI Workshop, December 3-4, 2003. Radiat Res 2004, 162(6): 711-728.

199. Pellmar TC, Rockwell S. Priority list of research areas for radiological nuclear threat countermeasures. Radiat Res 2005, 163(1): 115-123.

200. Romano MF, Lamberti A, Bisogni R, Garbi C, Pagnano AM, Auletta P, et al. Amifostine inhibits hematopoietic progenitor cell apoptosis by activating NF-kappaB/Rel transcription factors. Blood 1999, 94(12): 4060-4066.

201. Jakob U, Reichmann D. Oxidative Stress and Redox Regulation. Springer, 2013.

202. Copp RR, Fahl WE, Peebles DD. Amino thiol compounds and compositions for use in conjunction with cancer therapy. Google Patents; 2005.

203. Weiss JF, Hoover RL, Kumar KS. Selenium pretreatment enhances the radioprotective effect and reduces the lethal toxicity of WR-2721. Free Radic Res Commun 1987, 3(1-5): 33-38.

204. Kretz-Remy C, Arrigo AP. Selenium: a key element that controls NF-kappa B activation and I kappa B alpha half life. Biofactors 2001, 14(1-4): 117-125.



207. Ghosh SP, Perkins MW, Hieber K, Kulkarni S, Kao TC, Reddy EP, et al. Radiation protection by a new chemical entity, Ex-Rad: efficacy and mechanisms. Radiat Res 2009, 171(2): 173-179.

208. Burdelya LG, Krivokrysenko VI, Tallant TC, Strom E, Gleiberman AS, Gupta D, et al. An agonist of toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 2008, 320(5873): 226-230.

209. Burdelya LG, Brackett CM, Kojouharov B, Gitlin, II, Leonova KI, Gleiberman AS, et al. Central role of liver in anticancer and radioprotective activities of Toll-like receptor 5 agonist. Proc Natl Acad Sci U S A 2013, 110(20): E1857-1866.

210. Shakhov AN, Gudkov A. Methods of protecting against apoptosis using lipopeptides. Google Patents; 2007.

211. Shakhov AN, Singh VK, Bone F, Cheney A, Kononov Y, Krasnov P, et al. Prevention and mitigation of acute radiation syndrome in mice by synthetic lipopeptide agonists of Toll-like receptor 2 (TLR2). PLoS One 2012, 7(3): e33044.

212. Singh VK, Ducey EJ, Fatanmi OO, Singh PK, Brown DS, Purmal A, et al. CBLB613: a TLR 2/6 agonist, natural lipopeptide of Mycoplasma arginini , as a novel radiation countermeasure. Radiat Res 2012, 177(5): 628-642.

213. Whitnall MH, Villa V, Seed TM, Benjack J, Miner V, Lewbart ML, et al. Molecular specificity of 5-androstenediol as a systemic radioprotectant in mice. Immunopharmacol Immunotoxicol 2005, 27(1): 15-32.

214. Stickney DR, Dowding C, Authier S, Garsd A, Onizuka-Handa N, Reading C, et al. 5-androstenediol improves survival in clinically unsupported rhesus monkeys with radiation-induced myelosuppression. Int Immunopharmacol 2007, 7(4): 500-505.

215. Whitnall MH, Wilhelmsen CL, McKinney L, Miner V, Seed TM, Jackson WE, 3rd. Radioprotective efficacy and acute toxicity of 5-androstenediol after subcutaneous or oral administration in mice. Immunopharmacol Immunotoxicol 2002, 24(4): 595-626.

216. Kiang JG, Smith JT, Agravante NG. Geldanamycin analog 17-DMAG inhibits iNOS and caspases in gamma-irradiated human T cells. Radiat Res 2009, 172(3): 321-330.

217. Gorbunov NV, Kiang JG. Up-regulation of autophagy in small intestine Paneth cells in response to total-body gamma-irradiation. J Pathol 2009, 219(2): 242-252.

218. Mettler FA, Jr., Voelz GL. Major radiation exposure--what to expect and how to respond. N Engl J Med 2002, 346(20): 1554-1561.

219. Gandhi NM, Nair CK. Radiation protection by diethyldithiocarbamate: protection of membrane and DNA in vitro and in vivo against gamma-radiation. J Radiat Res 2004, 45(2): 175-180.

220. Neta R. Role of cytokines in radioprotection. Pharmacol Ther 1988, 39(1-3): 261-266.

221. Neta R, Monroy R, MacVittie TJ. Utility of interleukin-1 in therapy of radiation injury as studied in small and large animal models. Biotherapy 1989, 1(4): 301-311.

222. Okunieff P, Wu T, Huang K, Ding I. Differential radioprotection of three mouse strains by basic or acidic fibroblast growth factor. Br J Cancer Suppl 1996, 27: S105-108.

223. Zhang M, Qian J, Xing X, Kong FM, Zhao L, Chen M, et al. Inhibition of the tumor necrosis factor-alpha pathway is radioprotective for the lung. Clin Cancer Res 2008, 14(6): 1868-1876.

224. Mickelson AB, Horoho PD, Institute B. Medical Consequences of Radiological and Nuclear Weapons. U.S. Government Printing Office, 2013.

225. Gupta D, Arora R, Mohan RR, Almasan AA, Gudkov AV, Macklis RM. Novel Strategies for protecting mitochondria (the cellular powerhouse) against Low-LET radiation: A review. In: Arora R (ed). Herbal Radiomodulators: Application in Medicine, Homeland Defence & Space. CAB International, UK: Oxfordshire, 2008, pp 215-226.

226. Gupta D, Arora R, Garg AP, Goel HC. Radiation protection of HepG2 cells by Podophyllum hexandrum Royale. Molecular and cellular biochemistry 2003, 250(1-2): 27-40.

227. Chawla R, Arora R, Kumar R, Sharma A, Prasad J, Singh S, et al. Antioxidant activity of fractionated extracts of rhizomes of high-altitude Podophyllum hexandrum: role in radiation protection. Mol Cell Biochem 2005, 273(1-2): 193-208.

228. Mittal A, Pathania V, Agrawala PK, Prasad J, Singh S, Goel HC. Influence of Podophyllum hexandrum on endogenous antioxidant defence system in mice: possible role in radioprotection. J Ethnopharmacol 2001, 76(3): 253-262.

229. Sajikumar S, Goel HC. Podophyllum hexandrum prevents radiation-induced neuronal damage in postnatal rats exposed in utero. Phytother Res 2003, 17(7): 761-766.

230. Gupta D, Arora R, Garg AP, Bala M, Goel HC. Modification of radiation damage to mitochondrial system in vivo by Podophyllum hexandrum: mechanistic aspects. Mol Cell Biochem 2004, 266(1-2): 65-77.

231. Goel HC, Gupta D, Gupta S, Garg AP, Bala M. Protection of mitochondrial system by Hippophae rhamnoides L. against radiation-induced oxidative damage in mice. The Journal of pharmacy and pharmacology 2005, 57(1): 135-143.

232. Goel HC, Prasad J, Singh S, Sagar RK, Kumar IP, Sinha AK. Radioprotection by a herbal preparation of Hippophae rhamnoides, RH-3, against whole body lethal irradiation in mice. Phytomedicine 2002, 9(1): 15-25.

233. Goel HC, Salin CA, Prakash H. Protection of jejunal crypts by RH-3 (a preparation of Hippophae rhamnoides) against lethal whole body gamma irradiation. Phytother Res 2003, 17(3): 222-226.

234. Prasad NR, Menon VP, Vasudev V, Pugalendi KV. Radioprotective effect of sesamol on gamma-radiation induced DNA damage, lipid peroxidation and antioxidants levels in cultured human lymphocytes. Toxicology 2005, 209(3): 225-235.

235. Grotz KA, Henneicke-von Zepelin HH, Kohnen R, al-Nawas B, Bockisch A, Kutzner J, et al. [Prospective double-blind study of prophylaxis of radioxerostomia with Coumarin/Troxerutine in patients with head and neck cancer]. Strahlenther Onkol 1999, 175(8): 397-403; discussion 404.

236. Maurya DK, Salvi VP, Krishnan Nair CK. Radioprotection of normal tissues in tumor-bearing mice by troxerutin. J Radiat Res 2004, 45(2): 221-228.

237. Epperly M, Jin S, Nie S, Cao S, Zhang X, Franicola D, et al. Ethyl pyruvate, a potentially effective mitigator of damage after total-body irradiation. Radiat Res 2007, 168(5): 552-559.

238. Epperly MW, Greenberger JS, Mitchell PF. Radioprotective agents. Google Patents; 2007.

239. Liang X, Chavez AR, Schapiro NE, Loughran P, Thorne SH, Amoscato AA, et al. Ethyl pyruvate administration inhibits hepatic tumor growth. J Leukoc Biol 2009, 86(3): 599-607.

240. Herodin F, Drouet M. Cytokine-based treatment of accidentally irradiated victims and new approaches. Exp Hematol 2005, 33(10): 1071-1080.

241. Singh VK, Newman VL, Romaine PL, Wise SY, Seed TM. Radiation countermeasure agents: an update (2011-2014). Expert Opin Ther Pat 2014, 24(11): 1229-1255.

242. Glisson B, Komaki R, Lee JS, Shin DM, Fossella F, Murphy WK, et al. Integration of filgrastim into chemoradiation for limited small cell lung cancer: a Phase I study. Int J Radiat Oncol Biol Phys 1998, 40(2): 331-336.

243. Gava A, Bertossi L, Ferrarese F, Coghetto F, Marazzato G, Andrulli AD, et al. [Use of filgrastim, granulocyte colony stimulating factor (G-CSF), in radiotherapy to reduce drop-outs because of radiogenic leukopenia]. Radiol Med 1998, 95(3): 232-236.

244. Davis TA, Clarke TK, Mog SR, Landauer MR. Subcutaneous administration of genistein prior to lethal irradiation supports multilineage, hematopoietic progenitor cell recovery and survival. Int J Radiat Biol 2007, 83(3): 141-151.

245. Day RM, Barshishat-Kupper M, Mog SR, McCart EA, Prasanna PG, Davis TA, et al. Genistein protects against biomarkers of delayed lung sequelae in mice surviving high-dose total body irradiation. J Radiat Res 2008, 49(4): 361-372.

246. Singh VK, Grace MB, Parekh VI, Whitnall MH, Landauer MR. Effects of genistein administration on cytokine induction in whole-body gamma irradiated mice. Int Immunopharmacol 2009, 9(12): 1401-1410.

247. Raffoul JJ, Wang Y, Kucuk O, Forman JD, Sarkar FH, Hillman GG. Genistein inhibits radiation-induced activation of NF-kappaB in prostate cancer cells promoting apoptosis and G2/M cell cycle arrest. BMC Cancer 2006, 6: 107.

248. El-Missiry A, Othman AI, Alabdan A. Melatonin for Protection Against Ionizing Radiation. INTECH Open Access Publisher, 2012.

249. Mihandoost E, Shirazi A, Mahdavi SR, Aliasgharzadeh A. Can melatonin help us in radiation oncology treatments? Biomed Res Int 2014, 2014: 578137.

250. Carsten RE, Bachand AM, Bailey SM, Ullrich RL. Resveratrol reduces radiation-induced chromosome aberration frequencies in mouse bone marrow cells. Radiat Res 2008, 169(6): 633-638.

251. Fu Y, Wang Y, Du L, Xu C, Cao J, Fan T, et al. Resveratrol inhibits ionising irradiation-induced inflammation in MSCs by activating SIRT1 and limiting NLRP-3 inflammasome activation. Int J Mol Sci 2013, 14(7): 14105-14118.

252. Vorotnikova E, Rosenthal RA, Tries M, Doctrow SR, Braunhut SJ. Novel synthetic SOD/catalase mimetics can mitigate capillary endothelial cell apoptosis caused by ionizing radiation. Radiat Res 2010, 173(6): 748-759.

253. Doctrow SR, Lopez A, Schock AM, Duncan NE, Jourdan MM, Olasz EB, et al. A synthetic superoxide dismutase/catalase mimetic EUK-207 mitigates radiation dermatitis and promotes wound healing in irradiated rat skin. J Invest Dermatol 2013, 133(4): 1088-1096.

254. Prasad KN. Radiation Injury Prevention and Mitigation in Humans. Taylor & Francis, 2012.

255. Guney Y, Turkcu UO, Hicsonmez A, Andrieu MN, Guney HZ, Bilgihan A, et al. Carnosine may reduce lung injury caused by radiation therapy. Med Hypotheses 2006, 66(5): 957-959.

256. Tanaka RA, Ramos FM, Almeida SM, Vizioli MR, Boscolo FN. Evaluation of radioprotective effect of carnosine (beta- alanyl-1- histidine) on the wound healing in rats. J Appl Oral Sci 2005, 13(3): 253-258.

257. Chen T, Burke KA, Zhan Y, Wang X, Shibata D, Zhao Y. IL-12 facilitates both the recovery of endogenous hematopoiesis and the engraftment of stem cells after ionizing radiation. Exp Hematol 2007, 35(2): 203-213.

258. Basile L, Gallaher TK, Ellefson DD. Il-12 for radiation protection and radiation-induced toxicity mitigation. Google Patents; 2013.

259. Tse K, Horner AA. Update on toll-like receptor-directed therapies for human disease. Ann Rheum Dis 2007, 66 Suppl 3: iii77-80.

260. Tallant T, Deb A, Kar N, Lupica J, de Veer MJ, DiDonato JA. Flagellin acting via TLR5 is the major activator of key signaling pathways leading to NF-kappa B and proinflammatory gene program activation in intestinal epithelial cells. BMC Microbiol 2004, 4: 33.

261. Burdelya LG, Gleiberman AS, Toshkov I, Aygun-Sunar S, Bapardekar M, Manderscheid-Kern P, et al. Toll-like receptor 5 agonist protects mice from dermatitis and oral mucositis caused by local radiation: implications for head-and-neck cancer radiotherapy. Int J Radiat Oncol Biol Phys 2012, 83(1): 228-234.

262. Singh VK, Ducey EJ, Fatanmi OO, Singh PK, Brown DS, Purmal A, et al. CBLB613: A TLR 2/6 Agonist, Natural Lipopeptide of Mycoplasma arginini , as a Novel Radiation Countermeasure. Radiat Res 2011.

263. Huang WH, Lee AR, Chien PY, Chou TC. Synthesis of baicalein derivatives as potential anti-aggregatory and anti-inflammatory agents. J Pharm Pharmacol 2005, 57(2): 219-225.

264. Hwang JM, Tseng TH, Tsai YY, Lee HJ, Chou FP, Wang CJ, et al. Protective effects of baicalein on tert-butyl hydroperoxide-induced hepatic toxicity in rat hepatocytes. J Biomed Sci 2005, 12(2): 389-397.

265. Peng CY, Pan SL, Huang YW, Guh JH, Chang YL, Teng CM. Baicalein attenuates intimal hyperplasia after rat carotid balloon injury through arresting cell-cycle progression and inhibiting ERK, Akt, and NF-kappaB activity in vascular smooth-muscle cells. Naunyn Schmiedebergs Arch Pharmacol 2008, 378(6): 579-588.

266. Ha YM, Chung SW, Kim JM, Kim DH, Kim JY, Lee EK, et al. Molecular activation of NF-kappaB, pro-inflammatory mediators, and signal pathways in gamma-irradiated mice. Biotechnol Lett 2010, 32(3): 373-378.

267. von Holzen U, Pataer A, Raju U, Bocangel D, Vorburger SA, Liu Y, et al. The double-stranded RNA-activated protein kinase mediates radiation resistance in mouse embryo fibroblasts through nuclear factor kappaB and Akt activation. Clin Cancer Res 2007, 13(20): 6032-6039.

268. Bucur O, Stancu A, Muraru M, Melet A, Petrescu S, Khosravi-Far R. PLK1 is a binding partner and a negative regulator of FOXO3 tumor suppressor. Discoveries 2014, 2(2): e15.

269. Wang YY, Chen SM, Li H. Hydrogen peroxide stress stimulates phosphorylation of FoxO1 in rat aortic endothelial cells. Acta Pharmacol Sin 2010, 31(2): 160-164.

270. Lee EK, Kim JM, Choi J, Jung KJ, Kim DH, Chung SW, et al. Modulation of NF-kappaB and FOXOs by baicalein attenuates the radiation-induced inflammatory process in mouse kidney. Free Radic Res 2011, 45(5): 507-517.

271. Habraken Y, Piette J. NF-kappaB activation by double-strand breaks. Biochem Pharmacol 2006, 72(9): 1132-1141.

272. Lin Y, Ma W, Benchimol S. Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis. Nat Genet 2000, 26(1): 122-127.

273. Shen ZQ, Dong ZJ, Peng H, Liu JK. Modulation of PAI-1 and tPA activity and thrombolytic effects of corilagin. Planta Med 2003, 69(12): 1109-1112.

274. Duan W, Yu Y, Zhang L. Antiatherogenic effects of phyllanthus emblica associated with corilagin and its analogue. Yakugaku Zasshi 2005, 125(7): 587-591.

275. Kinoshita S, Inoue Y, Nakama S, Ichiba T, Aniya Y. Antioxidant and hepatoprotective actions of medicinal herb, Terminalia catappa L. from Okinawa Island and its tannin corilagin. Phytomedicine 2007, 14(11): 755-762.

276. Cheng JT, Lin TC, Hsu FL. Antihypertensive effect of corilagin in the rat. Can J Physiol Pharmacol 1995, 73(10): 1425-1429.

277. Zhao L, Zhang SL, Tao JY, Pang R, Jin F, Guo YJ, et al. Preliminary exploration on anti-inflammatory mechanism of Corilagin (beta-1-O-galloyl-3,6-(R)-hexahydroxydiphenoyl-D-glucose) in vitro. Int Immunopharmacol 2008, 8(7): 1059-1064.

278. Dong XR, Luo M, Fan L, Zhang T, Liu L, Dong JH, et al. Corilagin inhibits the double strand break-triggered NF-kappaB pathway in irradiated microglial cells. Int J Mol Med 2010, 25(4): 531-536.

279. Ghosh SP, Kulkarni S, Perkins MW, Hieber K, Pessu RL, Gambles K, et al. Amelioration of radiation-induced hematopoietic and gastrointestinal damage by Ex-RAD(R) in mice. J Radiat Res 2012, 53(4): 526-536.


News & Events Latest news from Discoveries

  • 2022, April| AWARDS!

    2022 Discoveries Award winning articles!

    - Kinal Bhatt et al. 2021 (Larking Health System, FL, USA); Bhatt K, Agolli A, Patel MH, et al. High mortality co-infections of COVID-19 patients: mucormycosis and other fungal infections. Discoveries. 2021;9(1):e126. 
    27 citations in the past 1 year - $1000 prize

    - Hasnain Jan et al. 2020 (Quaid-i-Azam University, Pakistan); Jan H, Faisal S, Khan A, et al. COVID-19: Review of Epidemiology and Potential Treatments Against 2019 Novel Coronavirus. Discoveries. 2020;8(2):e108. 
    23 citations in the past 2 years - $400 prize

    Congratulations! Prizes will be received by the awardees in July 2022!

  • 2021, July| 2021, Jul-September

    Due to the high volume of the submitted articles, both Discoveries and Discoveries Reports are experiencing processing and publication delays during the months of July-September 2021. We will get back to the normal processing and publication times starting in October 2021. Note that our editorial and administrativ work is fully funded by our publishing house at this time and we are striving to KEEP THE NO FEE/NO CHARGE strategy in place as long as possible. 

  • 2021, January| AWARDS!

    2022 DISCOVERIES AWARDS! Discoveries will offer $1000 and $400 awards in early 2022, for the most cited (2021 ISI Citations) and visible articles published in 2018-2021.

  • 2020, November| Follow us on Twitter!

    You can now follow the latest Discoveries news and updates on Twitter! (@DiscoveriesNews) 

  • 2020, August| For Authors!

    Due to a high volume of article submissions, our peer-review process takes more than usual. The pre-screening decision is released in 1-2 days, while the peer-review process lasts between 10 and 20 days.  

  • 2020, April | For Authors!

    WE DO NOT TOLERATE ANY MISCONDUCT! Please be aware that we are testing all received articles with specialized software for PLAGIARISM and WE WILL TAKE MEASURES if your article is already published or in consideration for publication by other journals! This may result in serious professional consequences for the authors. The latest striking case is the following article which is already published and was re-submitted here.  

  • 2020, April | For Authors!

    We are happy to let you know that all articles published in Discoveries are now included in PubMedCentral (PMC). New accepted articles will be included in PMC and PubMed within 1-2 weeks after their publication.

  • 2020, January | For Authors!

    Starting in January 2020, Discoveries will also consider articles submitted by Discoveries' Editorial Board members. However, only a small number of such articles (maximum 4 articles/year) will be considered for publication after the peer-review process, and the authors who are also our editors will be clearly disclosed on our website.  

  • 2019, September | Indexed by PMC

    Discoveries is now indexed by PubMedCentral and Pubmed. The agreement with US National Library of Medicine was signed on September 10, 2019. Our next step is ISI Web of Science indexing. NOTE: previously published articles will be included on PubMed in early 2020.

  • 2019, September | PubMed inclusion!

    We are happy to let you know that Discoveries successfuly passed the last step (Technical Review) required for PubMedCentral and PubMed inclusion!

  • 2019, July | PubMed inclusion News!

    We are happy to receive positive comments from PMC/NLM-NIH regarding Discoveries' last step (Technical Review) required for PubMedCentral and PubMed inclusion. We will let you know once whole indexing process is completed. 

  • 2019| Sharing and Distribution!

    All articles published in Discoveries are Open Access articles distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited and it is not used for commercial purposes.

  • 2018-2019 | For Authors!

    From now on and for at least 1 year, we will only accept articles from authors that are NOT members of Discoveries' Editorial Board. All articles submitted by our editors will be immediately rejected until further notice (one accepted article was already rejected). 

  • 2018 | PubMed inclusion News!

    Discoveries successfully passed the Scientific Quality Review by NLM-NIH for PubMedCentral and PubMed indexing. This is the first and the most important step towards PubMedCentral and PubMed indexing! The second (last) step is the Technical Review.

  • 2016, April | Faster Peer-Review

    Starting on April 13th 2016, all articles selected for a peer-review will receive the post peer-review decision within ~10 days. The initial pre-screening time will remain the same (48h from the submission of the manuscript). This decision will significantly accelerate the publication, with no effect on the quality of the peer-review process.

  • 2016, February | Manuscript submission

    Discoveries is commited to excellence, quality and high editorial standards. We are receiving an increasing number of manuscripts for which the identity of the authors/corresponding author can't be verified. Please NOTE that ALL these articles were and will be immediately REJECTED. Indicating an institutional email address is the easiest way to overcome this problem! Moreover, we do not accept any pressure on our editorial board to accept a manuscript. This results in a prompt rejection of the article.

    Editorial Policies
  • 2016, January | Main Objective

    After reaching all proposed milestones until now (including being indexed by Google Scholar in 2014), Discoveries' next Aim is PubMed indexing of all its articles (already published and upcoming). There will be no charge for the submission or publication of articles before Discoveries is indexed.

  • 2015, August | Discoveries - on PubMed

    We are happy to announce that our first Discoveries articles were included in PMC and PubMed. More articles (submitted by NIH funded authors) are now processed for being included.

    Discoveries articles now on PubMed
  • 2015, April | Special Issue

    DISCOVERIES published the SPECIAL ISSUE entitled "INFLAMMATION BETWEEN DEFENSE AND DISEASE: Impact on Tissue Repair and Chronic Sickness".

    Special Issue on "Inflammation"
  • 2015 | Ischemia Collection

    DISCOVERIES launched a call for papers for a Collection of Articles with focus on "ISCHEMIA". If you are interested to submit a manuscript, please contact us at info@discoveriesjournals.org

  • 2014, September | Special Issue

    DISCOVERIES just publish the SPECIAL ISSUE entitled "CELL SECRETION & MEMBRANE FUSION" in September 2014. Initially scheduled for publication between October 2014-March 2015, this issue was successfully published earlier than scheduled. 

    Special Issue
  • 2014, April | Indexed by Google Scholar

    All our published articles are now indexed by Google Scholar! First citations to Discoveries articles are included! Search for the article's title (recommended) or the authors:

    Google Scholar Search
  • 2014 | DISCOVERIES

    DOIs (Digital Object Identifiers) are now assigned to all our published manuscripts in Discoveries. DOI uniquely identifies an article and is provided by CrossRef.

  • 2013, July | Manuscript Submission

    Submit your manuscript FREE, FAST and EASY ! (in less than 1 minute)! There are NO fees for the manuscript submission or publishing of the accepted manuscripts.
    read more

  • 2013, July | DISCOVERIES

    We are now ACCEPTING MANUSCRIPTS for publishing in DISCOVERIES. We aim publishing a small number of high impact experimental articles & reviews (around 40/year) to maintain a high impact factor. Domains of interest: all areas related to Medicine, Biology and Chemistry ...

    read more
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