Radioprotector WR-2721 and mitigating peptidoglycan synergistically promote mouse survival through the amelioration of intestinal and bone marrow damage.
Bottom Line: Furthermore, combined PGN and WR-2721 treatment had an obviously synergistic radio-protective effect in nucleated cells in the bone marrow, including GEMM progenitors and CD45(+)CD34(+) cells 4 days after 10 Gy IR.The NF-κB p65 subunit was translocated to the nucleus, and phosphate-IκBα (Ser32/Ser36) was detected after stimulation with either PGN or WR-2721, which indicates that these two agents act synergistically through the activation of the NF-κB pathway.Administration of PGN in combination with WR-2721 was demonstrated to have a synergistic effect on the increase in haematopoietic cells and intestinal reconstitution, as well as improved survival in lethally irradiated mice, but resulted in some degree of an immune disorder.
Affiliation: School of Radiation Medicine and Protection, Soochow University, No. 199 Ren'ai Road, Suzhou 215123, PR China.Show MeSH
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Mentions: The bone marrow of unirradiated normal mice (N group) was highly cellular. After 10 Gy irradiation, mice exhibited a considerable decrease in the number of bone marrow cells and instead their bone marrow was full of red blood cells, especially four days post IR (IR group). Treatment with PGN (P group) or WR-2721 (W group) alleviated the bone marrow depletion by causing an increase in myelogenic cells, but WR-2721-treated mice exhibited haemorrhages (1.25 days post 10 Gy IR). In contrast, 4 days after irradiation, mice in the WR-2721 + PGN (W + P) group showed the presence of newly formed microvessels lined with endothelial cells, and small round haematopoietic cells were also apparent around the microvessels (Fig. 2A). The cell surface protein CD34 is frequently used as a marker for positive selection of haematopoietic progenitor cells in mouse bone marrow, both in research and in transplantation . At 1.25 days post IR, CD45+CD34+ cells were not drastically depleted. The proportion of CD45+CD34+ cells was evidently higher in the bone marrow of mice that received PGN treatment compared with untreated 10 Gy irradiated mice. On Day 4, CD45+CD34+ cells were drastically depleted, and the combination of WR2721 and PGN treatment was the most effective in restoring numbers of CD45+CD34+ cells. These results highlight the fact that WR-2721 + PGN treatment stimulated haematopoietic recovery, partially because it maintained a population of CD45+CD34+ haematopoietic cells (Fig. 2B).Fig. 2.
Affiliation: School of Radiation Medicine and Protection, Soochow University, No. 199 Ren'ai Road, Suzhou 215123, PR China.