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Radioprotector WR-2721 and mitigating peptidoglycan synergistically promote mouse survival through the amelioration of intestinal and bone marrow damage.

Liu W, Chen Q, Wu S, Xia X, Wu A, Cui F, Gu YP, Zhang X, Cao J - J. Radiat. Res. (2015)

Bottom Line: PGN-treated irradiated mice showed an increase in CD45(+)CD34(+) cells compared with untreated mice 1.25 days after 10 Gy ionizing radiation (IR) (P < 0.05).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.

View Article: PubMed Central - PubMed

Affiliation: School of Radiation Medicine and Protection, Soochow University, No. 199 Ren'ai Road, Suzhou 215123, PR China.

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WR-2721 + PGN combined treatment decreased bone marrow damage and increased numbers of CFU-GEMM and CD45+CD34+ cells. (A) Representative histological sections of the femur from mice in each of the 5 treatment groups at 1.25 and 4 days after 10 Gy WBI. N = unirradiated mice, IR = 10 Gy WBI mice, P = 10 Gy WBI mice treated with PGN, W = WR-2721-treated 10 Gy WBI mice, P + W = PGN and WR-2721 combination treated 10 Gy WBI mice (original magnification ×200). After 10 Gy irradiation, C57BL/6 mice could be seen to have lost most white cells in their bone marrow, and cavities in the bone marrow appeared. After single agent treatment with PGN or WR-2721, the numbers of nucleated cells increased, but haemorrhages appeared in the W group at 1.25 days and cavities still remained. On Day 4 post-IR, marrow microvessels appeared in femora of the P + W group and haematopoiesis commenced. (B) Number of CD45+CD34+ cells per 10 000 total cells from femoral marrow detected after red blood cells were removed using Zapoglobin, as analysed by fluorescence-activated cell sorting (FACS). On Day 1.25, only PGN-treated 10 Gy irradiated mice showed a marked increase in the proportion of CD34+CD45+ cells. On Day 4, the number of CD45+CD34+ cells was higher in the WR-2721 + PGN group than in other 10 Gy irradiated mice. (C) Only WR-2721 + PGN combined treatment induced growth of mouse CFU-GEMM haematopoietic progenitors following 10 Gy irradiation, and that growth was considerably subnormal on Days 4, 9, 16 and 25 days post IR. However, on Day 40, no marked difference between the W + P group and the N group was observed. Error bars indicate the SD for n = 10 mice (*P < 0.05).
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RRU100F2: WR-2721 + PGN combined treatment decreased bone marrow damage and increased numbers of CFU-GEMM and CD45+CD34+ cells. (A) Representative histological sections of the femur from mice in each of the 5 treatment groups at 1.25 and 4 days after 10 Gy WBI. N = unirradiated mice, IR = 10 Gy WBI mice, P = 10 Gy WBI mice treated with PGN, W = WR-2721-treated 10 Gy WBI mice, P + W = PGN and WR-2721 combination treated 10 Gy WBI mice (original magnification ×200). After 10 Gy irradiation, C57BL/6 mice could be seen to have lost most white cells in their bone marrow, and cavities in the bone marrow appeared. After single agent treatment with PGN or WR-2721, the numbers of nucleated cells increased, but haemorrhages appeared in the W group at 1.25 days and cavities still remained. On Day 4 post-IR, marrow microvessels appeared in femora of the P + W group and haematopoiesis commenced. (B) Number of CD45+CD34+ cells per 10 000 total cells from femoral marrow detected after red blood cells were removed using Zapoglobin, as analysed by fluorescence-activated cell sorting (FACS). On Day 1.25, only PGN-treated 10 Gy irradiated mice showed a marked increase in the proportion of CD34+CD45+ cells. On Day 4, the number of CD45+CD34+ cells was higher in the WR-2721 + PGN group than in other 10 Gy irradiated mice. (C) Only WR-2721 + PGN combined treatment induced growth of mouse CFU-GEMM haematopoietic progenitors following 10 Gy irradiation, and that growth was considerably subnormal on Days 4, 9, 16 and 25 days post IR. However, on Day 40, no marked difference between the W + P group and the N group was observed. Error bars indicate the SD for n = 10 mice (*P < 0.05).

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 [13]. 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.


Radioprotector WR-2721 and mitigating peptidoglycan synergistically promote mouse survival through the amelioration of intestinal and bone marrow damage.

Liu W, Chen Q, Wu S, Xia X, Wu A, Cui F, Gu YP, Zhang X, Cao J - J. Radiat. Res. (2015)

WR-2721 + PGN combined treatment decreased bone marrow damage and increased numbers of CFU-GEMM and CD45+CD34+ cells. (A) Representative histological sections of the femur from mice in each of the 5 treatment groups at 1.25 and 4 days after 10 Gy WBI. N = unirradiated mice, IR = 10 Gy WBI mice, P = 10 Gy WBI mice treated with PGN, W = WR-2721-treated 10 Gy WBI mice, P + W = PGN and WR-2721 combination treated 10 Gy WBI mice (original magnification ×200). After 10 Gy irradiation, C57BL/6 mice could be seen to have lost most white cells in their bone marrow, and cavities in the bone marrow appeared. After single agent treatment with PGN or WR-2721, the numbers of nucleated cells increased, but haemorrhages appeared in the W group at 1.25 days and cavities still remained. On Day 4 post-IR, marrow microvessels appeared in femora of the P + W group and haematopoiesis commenced. (B) Number of CD45+CD34+ cells per 10 000 total cells from femoral marrow detected after red blood cells were removed using Zapoglobin, as analysed by fluorescence-activated cell sorting (FACS). On Day 1.25, only PGN-treated 10 Gy irradiated mice showed a marked increase in the proportion of CD34+CD45+ cells. On Day 4, the number of CD45+CD34+ cells was higher in the WR-2721 + PGN group than in other 10 Gy irradiated mice. (C) Only WR-2721 + PGN combined treatment induced growth of mouse CFU-GEMM haematopoietic progenitors following 10 Gy irradiation, and that growth was considerably subnormal on Days 4, 9, 16 and 25 days post IR. However, on Day 40, no marked difference between the W + P group and the N group was observed. Error bars indicate the SD for n = 10 mice (*P < 0.05).
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RRU100F2: WR-2721 + PGN combined treatment decreased bone marrow damage and increased numbers of CFU-GEMM and CD45+CD34+ cells. (A) Representative histological sections of the femur from mice in each of the 5 treatment groups at 1.25 and 4 days after 10 Gy WBI. N = unirradiated mice, IR = 10 Gy WBI mice, P = 10 Gy WBI mice treated with PGN, W = WR-2721-treated 10 Gy WBI mice, P + W = PGN and WR-2721 combination treated 10 Gy WBI mice (original magnification ×200). After 10 Gy irradiation, C57BL/6 mice could be seen to have lost most white cells in their bone marrow, and cavities in the bone marrow appeared. After single agent treatment with PGN or WR-2721, the numbers of nucleated cells increased, but haemorrhages appeared in the W group at 1.25 days and cavities still remained. On Day 4 post-IR, marrow microvessels appeared in femora of the P + W group and haematopoiesis commenced. (B) Number of CD45+CD34+ cells per 10 000 total cells from femoral marrow detected after red blood cells were removed using Zapoglobin, as analysed by fluorescence-activated cell sorting (FACS). On Day 1.25, only PGN-treated 10 Gy irradiated mice showed a marked increase in the proportion of CD34+CD45+ cells. On Day 4, the number of CD45+CD34+ cells was higher in the WR-2721 + PGN group than in other 10 Gy irradiated mice. (C) Only WR-2721 + PGN combined treatment induced growth of mouse CFU-GEMM haematopoietic progenitors following 10 Gy irradiation, and that growth was considerably subnormal on Days 4, 9, 16 and 25 days post IR. However, on Day 40, no marked difference between the W + P group and the N group was observed. Error bars indicate the SD for n = 10 mice (*P < 0.05).
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 [13]. 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.

Bottom Line: PGN-treated irradiated mice showed an increase in CD45(+)CD34(+) cells compared with untreated mice 1.25 days after 10 Gy ionizing radiation (IR) (P < 0.05).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.

View Article: PubMed Central - PubMed

Affiliation: School of Radiation Medicine and Protection, Soochow University, No. 199 Ren'ai Road, Suzhou 215123, PR China.

Show MeSH
Related in: MedlinePlus