title: A Combination of Podophyllotoxin and Rutin Attenuates Radiation Induced Gastrointestinal Injury by Negatively Regulating NF-κB/p53 Signaling in Lethally Irradiated Mice.
abstract: Development of an effective radio protector to minimise radiation-inflicted damages have largely failed owing to inherent toxicity of most of the agents examined so far. This study is centred towards delivering protection to lethally irradiated mice by pre-administration of a safe formulation G-003M (combination of podophyllotoxin and rutin) majorly through regulation of inflammatory and cell death pathways in mice. Single intramuscular dose of G-003M injected 60 min prior to 9 Gy exposure rescued 89% of whole body lethally irradiated C57BL/6J mice. Studies have revealed reduction in radiation induced reactive oxygen species (ROS), nitric oxide (NO) generation, prostaglandin E2 (PGE2) levels and intestinal apoptosis in G-003M pre-treated mice intestine. Restricted nuclear translocation of redox-sensitive Nuclear factor-κB (NF-κB) and subsequent downregulation of cyclo-oxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS; EC 1.14.13.39) and tumor necrosis factor (TNF-α) levels demonstrated the anti-inflammatory effect that G-003M exerts. Support to early hematopoietic recovery was exhibited through G-003M mediated induction of granulocyte colony stimulating factor (G-CSF) and interleukin (IL-6) levels in lethally irradiated mice. Considerable attenuation in radiation induced morphological damage to the intestinal villi, crypts and mucosal layers was observed in G-003M pre-treated mice. Additionally, our formulation did not reduce the sensitivity of tumor tissue to radiation. Altogether, these results suggest that G-003M ameliorates the deleterious effects of radiation exposure by minimising ROS and NO generation and effectively regulating inflammatory and cell death pathways. Mechanism of protection elucidated in the current study demonstrates that G-003M can be used as a safe and effective radio protective agent in radiotherapy for human application.
authors.affiliation: Division of Radioprotective Drug Development and Research, Institute of Nuclear Medicine and Allied Sciences, Brig.S.K Mazumdar Marg, Delhi, INDIA.
authors.forename: Bhargab
authors.initials: B
authors.lastname: Kalita
authors.affiliation: Division of Radioprotective Drug Development and Research, Institute of Nuclear Medicine and Allied Sciences, Brig.S.K Mazumdar Marg, Delhi, INDIA.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Ranjan
authors.affiliation: Division of Radioprotective Drug Development and Research, Institute of Nuclear Medicine and Allied Sciences, Brig.S.K Mazumdar Marg, Delhi, INDIA.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Singh
authors.affiliation: Division of Radioprotective Drug Development and Research, Institute of Nuclear Medicine and Allied Sciences, Brig.S.K Mazumdar Marg, Delhi, INDIA.
authors.forename: M H
authors.initials: MH
authors.lastname: Yashavarddhan
authors.affiliation: Division of Radioprotective Drug Development and Research, Institute of Nuclear Medicine and Allied Sciences, Brig.S.K Mazumdar Marg, Delhi, INDIA.
authors.forename: Sania
authors.initials: S
authors.lastname: Bajaj
authors.affiliation: Division of Radioprotective Drug Development and Research, Institute of Nuclear Medicine and Allied Sciences, Brig.S.K Mazumdar Marg, Delhi, INDIA.
authors.forename: Manju Lata
authors.initials: ML
authors.lastname: Gupta
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004359:Drug Therapy, Combination / Q000379:methods; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000528:radiation effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011034:Podophyllotoxin / Q000494:pharmacology*; D011832:Radiation Injuries / Q000188:drug therapy* / Q000378:metabolism*; D011837:Radiation-Protective Agents; D017382:Reactive Oxygen Species / Q000378:metabolism; D012431:Rutin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D011837:Radiation-Protective Agents; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; D012431:Rutin; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D011034:Podophyllotoxin