title: The combination of the active principles of Podophyllum hexandrum supports early recovery of the gastrointestinal system via activation of Nrf2-HO-1 signaling and the hematopoietic system, leading to effective whole-body survival in lethally irradiated mice.
abstract: This study is aimed at the development of a safe radioprotective formulation to minimize human sufferings during accidental nuclear exposures. In the current study, a combination of three active principles, namely podophyllotoxin, podophyllotoxin beta-D-glucoside, and rutin (G-002M), isolated from Podophyllum hexandrum rhizomes, has been evaluated for its radioprotective potential and mode of action. Total body protection studies have demonstrated that a single prophylactic dose of G-002M delivered more than 85% survival in mice exposed to a lethal (9 Gy) dose of gamma radiation, and significantly protected the radiosensitive hematopoietic and gastrointestinal organs. Studies have also revealed a reduction in free radical generation, lipid peroxidation, protein carbonylation, and cell death in mouse intestine after G-002M treatment, while GSH was observed to be enhanced in the same tissue. Redox-sensitive transcription factor (Nrf2) activation and subsequent upregulation of heme oxygenase-1 (HO-1) and SOD-1 revealed the cytoprotective role of G-002M. A histological examination of the jejunum pretreated with the formulation also demonstrated less damage to the villi, crypts, and the mucosal layers. These observations reiterated that the reduction in the ROS levels, protection of cellular macromolecules, and activation of the antioxidant signaling pathway may have been the principle factors involved in G-002M- mediated protection against radiation-induced tissue impairment. The potentially safe and effective radioprotective characteristics of this new combination are encouraging for further studies for human application.
authors.affiliation: Division of Radiation Biosciences, Department of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences , Delhi , India.
authors.forename: A
authors.initials: A
authors.lastname: Dutta
authors.forename: M L
authors.initials: ML
authors.lastname: Gupta
authors.forename: B
authors.initials: B
authors.lastname: Kalita
mesh_terms: D000818:Animals; D005720:Gamma Rays; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000528:radiation effects*; D006413:Hematopoietic System / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000494:pharmacology*; D011035:Podophyllum / Q000737:chemistry; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D012431:Rutin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014916:Whole-Body Irradiation
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010936:Plant Extracts; D011837:Radiation-Protective Agents; D012431:Rutin; D051547:Heme Oxygenase-1; D011034:Podophyllotoxin
keywords: Nrf2; Podophyllum hexandrum; ionizing radiation; oxidative stress; radioprotector