title: Concerted action of Nrf2-ARE pathway, MRN complex, HMGB1 and inflammatory cytokines - implication in modification of radiation damage.
abstract: Whole body exposure to low linear energy transfer (LET) ionizing radiations (IRs) damages vital intracellular bio-molecules leading to multiple cellular and tissue injuries as well as pathophysiologies such as inflammation, immunosuppression etc. Nearly 70% of damage is caused indirectly by radiolysis of intracellular water leading to formation of reactive oxygen species (ROS) and free radicals and producing a state of oxidative stress. The damage is also caused by direct ionization of biomolecules. The type of radiation injuries is dependent on the absorbed radiation dose. Sub-lethal IR dose produces more of DNA base damages, whereas higher doses produce more DNA single strand break (SSBs), and double strand breaks (DSBs). The Nrf2-ARE pathway is an important oxidative stress regulating pathway. The DNA DSBs repair regulated by MRN complex, immunomodulation and inflammation regulated by HMGB1 and various types of cytokines are some of the key pathways which interact with each other in a complex manner and modify the radiation response. Because the majority of radiation damage is via oxidative stress, it is essential to gain in depth understanding of the mechanisms of Nrf2-ARE pathway and understand its interactions with MRN complex, HMGB1 and cytokines to increase our understanding on the radiation responses. Such information is of tremendous help in development of medical radiation countermeasures, radioprotective drugs and therapeutics. Till date no approved and safe countermeasure is available for human use. This study reviews the Nrf2-ARE pathway and its crosstalk with MRN-complex, HMGB1 and cytokines (TNF-a, IL-6, IFN-? etc.). An attempt is also made to review the modification of some of these pathways in presence of selected antioxidant radioprotective compounds or herbal extracts.
authors.affiliation: Radiation Biology Department, Institute of Nuclear Medicine and Allied Sciences, Brig SK Mazumdar Marg, Delhi -110054, India.
authors.lastname: Anuranjani
authors.affiliation: Radiation Biology Department, Institute of Nuclear Medicine and Allied Sciences, Brig SK Mazumdar Marg, Delhi -110054, India.
authors.forename: Madhu
authors.initials: M
authors.lastname: Bala
mesh_terms: D061745:Antioxidant Response Elements / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004249:DNA Damage / Q000528:radiation effects*; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D024243:HMGB1 Protein / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018797:Cell Cycle Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D024243:HMGB1 Protein; D051267:NF-E2-Related Factor 2; D045643:DNA Repair Enzymes
keywords: .OH, hydroxyl radical; AP1, activator protein-1; ARE, antioxidant response element; ATM, ataxia telangiectasia mutagenesis; Bcl-2, B cell lymphoma-2 protein; CBP, CREB-binding protein; Chk-2, checkpoint kinase-2 protein; DAMP, death associated molecular pattern; DDR, DNA damage response; DGR, double glycine repeats; DSB, double strands break; FGF, fibroblast growth factor; FGF2, fibroblast growth factor-2; GM-CSF, granulocytes macrophages colony stimulating factor; GPx, glutathione peroxidase; GSH, glutathione (reduced); GSK-3ß, glycogen synthase kinase 3 beta; HMGB1; HMGB1, high mobility group Box 1; HR, homologous recombination; IR, ionizing radiation; Keap1, Kelch like ECH associated protein 1; LET, linear energy transfer; MDA, malondialdehyde; MIP, macrophages inflammatory proteins; MRN complex; MRN, Mre11, Rad50 and Nbs1 subunits; MRP, multidrug resistance protein; NADPH, nicotinamide adenine dinucleotide phosphate; NES, nuclear export sequence; NHEJ, non-homologous end joining; NLS, nuclear localization sequence; Nrf2-ARE pathway; PKC, protein kinase C; RAGE, receptor for advance glycation end products; RIF, radiation induced foci; RNS, reactive nitrogen species; ROS, reactive oxygen species; Radio-modification; SOD, superoxide dismutase; SSBs, single strand DNA breaks; TRAIL, TNF related apoptosis inducing ligand; TWEAK; TWEAK, tumour necrosis factor weak inducer of apoptosis; VEGF, vascular endothelial growth factor; VSMC, vascular smooth muscle cells; bFGF, basal fibroblast growth factor; t-BHQ, tert butyl hydroquinone