Fig 2: Accumulation of reactive oxygen species triggered by SD between the non-SD group and SD group in mouse ELGs. (A) Heatmaps of diurnal expression for reactive oxygen-related genes between the non-SD group and SD group in mouse ELGs. The expression levels of reactive oxygen-related genes were obtained from RNA-Seq and expression range was normalized to ±3. (B) Representative images of ROS levels are shown in the ZT0, ZT6, ZT12, and ZT18 after SD between the non-SD group and SD group in mouse ELGs. Scale bar: 50 µm. (C) Quantification of ROS levels in ELGs from SD and non-SD-treated mice at six-hour intervals (non-SD: F = 10.079, P < 0.001; SD: F = 0.442, P > 0.05). Each time point shows the median and SEM of biological samples. **P < 0.01, ***P < 0.001. (D) Average quantification of ROS levels in ELGs from SD and non-SD-treated mice. ***P < 0.001. (E) Representative images of nitrotyrosine levels are shown in the ZT0 after SD between the non-SD group and SD group in mouse ELGs. Scale bar: 20 µm. (F) Quantification of nitrotyrosine levels in ELGs from SD and non-SD-treated mice at six-hour intervals (non-SD-treated mice: F = 6.140, P < 0.01; SD-treated mice: F = 40.561, P < 0.001). Each time point shows the median and SEM of biological samples. **P < 0.01, ***P < 0.001. (G) Average quantification of nitrotyrosine levels in ELGs from SD and non-SD-treated mice. ***P < 0.001. (H) Representative images of γ-H2Ax levels are shown in the ZT0, ZT6, ZT12, and ZT18 after SD between the non-SD group and SD group in mouse ELGs. Scale bar: 50 µm. (I) Quantification of γ-H2Ax levels in ELGs from SD and non-SD-treated mice at six-hour intervals (non-SD-treated mice: F = 77.252, P < 0.001; SD-treated mice: F = 49.237, P < 0.001). Each time point shows the median and SEM of biological samples. **P < 0.01, ***P < 0.001. (J) Average quantification of γ-H2Ax levels in ELGs from SD and non-SD-treated mice. ***P < 0.001.

Fig 3: METi‐induced modulation of selected phosphorylations is time‐dependent and partially ATM‐dependent. (A) Impact of METi pretreatment duration (6 or 16 h prior to IR) and ATM activity (ATM was inhibited 6 or 1 h prior or 1 h post‐IR) on phosphorylation of MET, ATM, NUMA1, H2AX, CHEK1, and TIF1B, on cleavage of caspase‐8 and on CHEK1 protein levels. Cells were harvested 2 h post‐IR, and β‐actin was used as a loading control. (B) METi‐ and ATMi‐based modulation of cellular phosphorylations measured by SRM in EBC‐1 cells. Listed assays have been monitored in samples treated with ATMi, METi, IR, or the combinations (METi + IR; ATMi + METi + IR). Here are presented the results from statistical comparisons addressing three questions: Which are the significant changes in response to IR alone, compared with control (left); which are the significant changes in response to the combination METi + IR, compared with IR alone (right); and which are the significant changes in response to the combination ATMi + METi + IR, compared with METi + IR (middle). Log2FC (n = 3) is represented by a color code; adjusted P‐values by symbol: <0.0005, ‘***’, <0.005, ‘**’, <0.05, ‘*’. (C) Log2FC per condition is presented in comparison with control sample (untreated) for selected phosphorylation events in EBC‐1 cells upon IR (1 or 8 h) with or without METi and/or ATMi pretreatment as compared to untreated condition (n = 3).

Fig 4: The impact of oral uptake of altertoxin-II (ATX-II) or a complex extract (CE) of Alternaria toxins on H2a.X phosphorylation and depletion in the colon of rats, at 3 h or 24 h after administration, as measured by SDS-PAGE/Western Blotting. (A,B) depict protein levels of H2a.X and its phosphorylated form, pH2a.X, respectively, as box blots and data points for the single rats. Likewise, the ratio of phosphorylated to native H2a.X levels for each rat are displayed in (C). All data was normalized to the respective control (Ctrl) rat receiving the solvent that was analyzed in the same experiment, as indicated by dotted lines. Normal distribution of data was confirmed by Shapiro-Wilk testing. Significant differences to the control group were calculated using one-way ANOVA, followed by Fisher LSD post-hoc testing, and are indicated by “*” (p < 0.05) or “**” (p < 0.01). In case one-way ANOVA gave inconsistent results due to the high variability within other groups, significance testing was repeated using Student’s t-test against the control group, with positives indicated by “#” (p < 0.05). A representative image of membranes of one experiment is given in sub-Panel (D).

Fig 5: MRIAN‐Dox has reduced cardiotoxicity and tissue damage than Dox. a) Scheme for synthesizing of MRIAN‐Dox. b) Time‐dependent stability of MRIAN‐Dox in PBS or PBS with 10% fetal bovine serum (FBS). c,d) Scheme (c) and pharmacokinetics of Dox and MRIAN‐Dox in mice (d). e) Treatment scheme for T‐cell acute lymphoblastic leukemia (T‐ALL) mice. f–i) HE, Masson staining, representative immunohistochemistry images of TUNEL, γ‐H2AX (f), quantification of the fibrostic area (g), γ‐H2AX+ cells frequency (h), and Tunel+ cells frequency (i) in the heart section of hearts from T‐ALL mice after indicated treatments (n = 5 mice). j–l) M‐mode echocardiography (j), quantification of ejection fraction (k), and fractional shortening (l) of T‐ALL mice after indicated treatments (n = 5 mice). m,n) HE of kidney or liver (m) and quantification of glomerular necrosis frequency in the kidney (left) and liver function ALT (middle) and AST (right) in mice serum after indicated treatments. Repeated measures one‐way analysis of variance (ANOVA) followed by Dunnett's test for multiple comparisons, ǂ p < 0.05, ǂǂ p < 0.01, ǂǂǂ p < 0.001.