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1.
Fig. P1.

Fig. P1. From: Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells from ionizing radiation.

Pretreatment with a synthetic triterpenoid before IR activates Nrf2, which regulates transcription of the antioxidant enzyme HO-1 and the DNA repair protein, p53 binding protein-1 (53BP1). Increased levels of HO-1 and 53BP1 protect colonic epithelial cells from IR-induced DNA damage and apoptosis.

Sang Bum Kim, et al. Proc Natl Acad Sci U S A. 2012 October 23;109(43):E2949-E2955.
2.
Fig. 4.

Fig. 4. From: Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells from ionizing radiation.

Nrf2 increases 53BP1 expression by BARD treatment. ChIP-qPCR analysis of Nrf2 occupancy on the 53BP1 (A) and HO-1 (B) promoters using unirradiated cells following treatment with vehicle or BARD for 18 h. Data shown are from two separate triplicate experiments. (C) Quantitation of 53BP1 mRNA levels by RT-qPCR analysis showing increase of 53BP1 expression with BARD treatment for 18 h. Data shown are from two separate experiments and are normalized to GAPDH. (D) Quantitation of Western blot analysis showing increase of 53BP1 with BARD treatment for 18 h. Data shown are from two separate experiments and are normalized to β-actin. *P < 0.05 and **P < 0.005 (compared with vehicle control) in the unpaired Student t test; ns, not significant differences in the unpaired Student t test.

Sang Bum Kim, et al. Proc Natl Acad Sci U S A. 2012 October 23;109(43):E2949-E2955.
3.
Fig. 1.

Fig. 1. From: Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells from ionizing radiation.

BARD protects HCECs from irradiation through Nrf2. (A) Clonogenic survival for countermeasure effect. HCECs were treated with BARD for 18 h, and cells were then irradiated with the indicated radiation doses. (B) Establishment of Nrf2 knockdown cell lines. HCEC CT7s were infected by a lentiviral vectors expressing a shRNA against Nrf2 and were treated with or without BARD. Cell extracts were separated by SDS/PAGE and blotted using anti-Nrf2 or anti–HO-1 antibody. (C) Clonogenic survival of control or Nrf2 knockdown cell line. HCEC CT7/short hairpin Nrf2 (shNrf2) cells were treated with BARD for 18 h and were then irradiated with the indicated radiation doses. *P < 0.05 compared with vehicle control; ns, not significant differences in the unpaired Student t test; shCtrl, short hairpin control.

Sang Bum Kim, et al. Proc Natl Acad Sci U S A. 2012 October 23;109(43):E2949-E2955.
4.
Fig. 5.

Fig. 5. From: Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells from ionizing radiation.

CDDO-EA increases mouse survival after an acute lethal dose of TBI. (A) CDDO-EA stabilizes and activates Nrf2 in mouse colon tissues. A CDDO-EA diet was provided to unirradiated WT mice for 1, 2, or 3 d, and the colon tissues were then lysed. Total Nrf2 and phospho-Nrf2 (p-Nrf2) were detected by Western blot analysis (Fig. S6; n = 3). (B) Groups of 129/Sv female mice were fed the CDDO-EA diet or control chow 3 d before 7.5-Gy TBI. Pooled results from two independent experiments are shown. Note a significant (within 95% confidence interval) increase in median survival in CDDO-EA–treated mice (21.5 d) compared with vehicle control (13 d).

Sang Bum Kim, et al. Proc Natl Acad Sci U S A. 2012 October 23;109(43):E2949-E2955.
5.
Fig. 3.

Fig. 3. From: Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells from ionizing radiation.

BARD increases DNA damage signaling. Effect of BARD on appearance and disappearance of DNA damage-associated repairosome foci of CtIP (A) and 53BP1 (B) after 5-Gy doses of IR. (C) Rad51-positive cells with vehicle or BARD 4 h after 5-Gy doses of IR. For each point, 200 cells were counted, and the mean of three experiments is given in the figures. (D) Western blot of Rad51 and BRCA1 levels in the nuclear fraction of HCECs 30, 60, and 120 min after 5-Gy doses of IR with or without BARD pretreatment. 53BP1 foci-positive cells (E) and nuclear localization of Rad51 (F) in Nrf2 knockdown cell line 60 min after 5-Gy doses of IR. *P < 0.05 (compared with vehicle control) in the unpaired Student t test. shCtrl, short hairpin control; shNrf2, short hairpin Nrf2.

Sang Bum Kim, et al. Proc Natl Acad Sci U S A. 2012 October 23;109(43):E2949-E2955.
6.
Fig. 2.

Fig. 2. From: Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells from ionizing radiation.

BARD reduces chromosome aberrations and releases DNA replication block after IR. Chromosome aberrations were studied at metaphase postirradiation. (A) G1-type aberrations were analyzed at metaphase 14 h after exposure to 5 Gy of IR (Fig. S1A). The histogram shows the G1-chromosome aberrations. (B) S- and G2-type chromosomal aberrations were analyzed at metaphases after 4 Gy of IR. Cells were exposed to 4 Gy of IR and collected at different times points to analyze S- or G2-type aberrations (Fig. S1B). The histogram shows S- and G2-type chromosomal aberrations per metaphase. For each phase, 50 metaphases were analyzed from two independent experiments for each phase of the cell cycle. The mean of four experiments is presented in the histogram. (C and D) The restart of replication forks was analyzed using DNA fiber assay. The percentages of stalled forks (C) and new origins of replication (D) were measured at various time points posttreatment with HU. For each experiment, 100 fibers were analyzed in different sections of the slides. The results are the mean of three experiments. *P < 0.05 (compared with vehicle control) in the unpaired Student t test.

Sang Bum Kim, et al. Proc Natl Acad Sci U S A. 2012 October 23;109(43):E2949-E2955.
7.
Fig. 6.

Fig. 6. From: Targeting of Nrf2 induces DNA damage signaling and protects colonic epithelial cells from ionizing radiation.

CDDO-EA protects the GI tract from acute TBI. (A) Representative images of H&E staining of the colon tissue in different strains at 5 d after TBI with or without prior feeding of CDDO-EA chow. (B) Length of villi (left y axis) were measured in at least 40 complete, well-oriented villi cross-sections in the small intestine of 129/Sv mice 5 d after a 7.5-Gy dose of TBI. Crypt number per 1-mm length of the small intestine was counted (right y axis) (n = 3). (CF) WT C57BL/6 mice were exposed to 10-Gy TBI 3 d after feeding of control or CDDO-EA chow. Representative TUNEL staining (green fluorescence) in the colon (C; 1 d postirradiation) and immunohistochemical detection of in vivo BrdU incorporation (green fluorescence) in the colon crypts (D; 3 d postirradiation) are shown. DAPI (blue) or smooth muscle actin (red fluorescence) was used for counterstaining. (E) BrdU-positive cells were counted in 15 complete, well-oriented crypt cross-sections (n = 3). The dashed line indicates the number of BrdU-positive cells considered critical for crypt survival (47). (F) Colon tissues were immunostained using anti-53BP1 antibodies 1, 3, or 5 d after a 10-Gy dose of TBI. (Left) Representative images show 53BP1-positive cells in colon tissues. DAPI was used for counterstaining (Fig. S7). (Right) Number of 53BP1-positive cells was counted in at least 60 complete, well-oriented crypt cross-sections in the colon (n = 3). *P < 0.0001 and **P = 0.0016 (compared with vehicle control) in the unpaired Student t test.

Sang Bum Kim, et al. Proc Natl Acad Sci U S A. 2012 October 23;109(43):E2949-E2955.

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