Combination of natural polyphenols with a precursor of NAD+ and a TLR2/6 ligand lipopeptide protects mice against lethal y radiation

Introduction: Effective agents that could confer long-term protection against ionizing radiation in vivo would have applications in medicine, biotechnology, and in air and space travel. However, at present, drugs that can effectively protect against lethal ionizing radiations are still an unmet need. Objective: To investigate if combinations of natural polyphenols, known for their antioxidant potential, could protect against ionizing radiations. Methods: Plant-derived polyphenols were screened for their potential ability to confer radioprotection to mice given a lethal whole-body 7 radiation (137Cs) dose expected to kill 50% of the animals in 30 days. Telomere and centromere staining, Q-FISH and comet assays were used to investigate chromosomal aber-ration, micronuclei formation and DNA breaks. Molecular oxidations were investigated by enzyme immunoassays and UPLC-MS/MS. RT-PCR, western blotting and siRNA-induced gene silencing were used to study signaling mechanisms and molecular interactions. Results: The combination of pterostilbene (PT) and silibinin (SIL) was the most effective against 7 -irradiation, resulting in 100% of the mice surviving at 30 days and 20% survival at one year. Treatment post 7-irradiation with two potential radiomitigators nicotinamide riboside (NR, a vitamin B3 derivative), and/or fibroblast-stimulating lipoprotein 1 (FSL1, a toll-like receptor 2/6 agonist), did not extend survival. However, the combination of PT, SIL, NR and FSL1 achieved a 90% survival one year post 7-irradiation. The mechanism involves induction of the Nrf2-dependent cellular antioxidant defense, reduction of NF-kB signaling, upregulation of the PGC-1a/sirtuins 1 and 3 axis, PARP1-dependent DNA repair, and stimula-tion of hematopoietic cell recovery. The pathway linking Nrf2, sirtuin 3 and SOD2 is key to radioprotec-tion. Importantly, this combination did not interfere with X-ray mediated killing of different tumor cells in vivo. Conclusion: The combination of the radioprotectors PT and SIL with the radiomitigators NR and FSL1 con-fer effective, long-term protection against 7 radiation in vivo. This strategy is potentially capable of pro-tecting mammals against ionizing radiations. (c) 2023 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

The combination of natural polyphenols PT and SIL with radiomitigators NR and FSL1 can effectively protect animals from ionizing radiation.