Journal: CNS Neuroscience & Therapeutics

Article Title: Aerobic Exercise Promotes Hippocampal Neurogenesis and Ameliorates Cognitive Dysfunction Induced by Unilateral Labyrinthectomy

doi: 10.1002/cns.70773

Figure Lengend Snippet: AZD1480 ameliorates UL‐induced cognitive dysfunction, whereas LPS significantly counteracts the cognitive improvements conferred by running. (A) Schematic of the experimental design showing AZD1480 and LPS interventions in UL mice. (B, C) In the open field test, there were no significant differences in total movement distance and average speed among the four groups of mice: UL + Static + VH, UL + Static + AZD1480, UL + Run + VH, UL + Run + LPS (One‐way ANOVA: F (3,36) = 1.236, p = 0.3110, and F (3,36) = 1.257, p = 0.3037). (D, E) There were no significant intergroup differences in terms of total immobility time and the duration spent in the central zone of the open field for the UL + Static + VH, UL + Static + AZD1480, UL + Run + VH, UL + Run + LPS groups (One‐way ANOVA: F (3,36) = 1.780, p = 0.1684 and F (3,36) = 0.7831, p = 0.5112, n = 10/group in OFT). (F, G) AZD1480 ameliorated the UL‐induced working memory impairment, whereas LPS counteracts the cognitive improvements conferred by running, manifested by the total entry to and time spent in the novel arm. Right arm (F) was set as the novel arm (One‐way ANOVA: F (3,36) = 9.760, p < 0.0001), Tukey's multiple comparisons test: UL + Static + VH vs. UL + Static + AZD1480: p = 0.0011, UL + Static + VH vs. UL + Run + VH: p = 0.0036, UL + AZD1480 vs. UL + Run + LPS: p = 0.0022, UL + Run + VH vs. UL + Run + LPS: p = 0.0068 for the percentage of novel arms; One‐way ANOVA: F (3,36) = 15.93, p < 0.0001, Tukey's multiple comparisons test: UL + Static + VH vs. UL + Static + AZD1480: p < 0.0001, UL + AZD1480 vs. UL + Run + VH: p = 0.0056, UL + Static + AZD1480 vs. UL + Run + LPS: p < 0.0001 for the total time of the novel arms, Left arm (G) was set as the novel arms (One‐way ANOVA: F (3,36) = 2.814, p = 0.0529, Tukey's multiple comparisons test: UL + Static + VH vs. UL + Run + VH p = 0.0488, for the percentage of novel arms; One‐way ANOVA: F (3,36) = 7.771, p = 0.0004, Tukey's multiple comparisons test: UL + Static + VH vs. UL + Static + AZD1480: p = 0.0036, UL + Static + VH vs. UL + Run+ VH: p = 0.0005 for the total time of the novel arms, n = 10/group in T maze). (H) AZD1480 significantly improves the number of errors in UL‐induced reference memory, whereas LPS counteracts the cognitive improvements conferred by running (two‐way ANOVA: F (27,324) = 2.115, p = 0.0013, Tukey's multiple comparisons test: UL + Static + VH vs. UL + Static + AZD1480: p < 0.0001, UL + Static + VH vs. UL + Run + VH: p < 0.0001, UL + Static + AZD1480 vs. UL + Run + LPS: p < 0.0001, UL + Run + VH vs. UL + Run + LPS: p < 0.0001). (I) AZD1480 significantly reduces the number of errors in working memory induced by UL (two‐way ANOVA: F (27,324) = 1.623, p = 0.0283, Tukey's multiple comparisons test: UL + Static + VH vs. UL + Static + AZD1480: p < 0.0001, UL + Static + VH vs. UL + Run + VH: p = 0.0273, UL + Static + AZD1480 vs. UL + Run + LPS: p = 0.0006). (J) Total time to complete tasks decreased by aerobic exercise (two‐way ANOVA: F (27,324) = 3.394, p < 0.0001), Tukey's multiple comparisons test: UL + Static + VH vs. UL + Static + AZD1480: p = 0.0003, UL + Static + VH vs. UL + Run + VH: p = 0.0003, UL + Static + AZD1480 vs. UL + Run + LPS: p = 0.0001, UL + Run + VH vs. UL + Run + LPS: p = 0.0001, n = 10/group, data are presented as mean ± standard error of the mean (SEM). (K) Throughout the training, UL + Static + VH, UL + Static + AZD1480, UL + Run + VH and UL + Run + LPS mice froze at comparable level during the trace interval (two‐way ANOVA, F (3,72) = 0.5261, p = 0.6658). (L, M) AZD1480 and running resulted in improved contextual and tone‐cued fear conditioning, but LPS prevented the running‐induced improvement (One‐way ANOVA: F (3,36) = 17.34, p < 0.0001, Tukey's multiple comparisons test: UL + Static + VH vs. UL + Static + AZD1480: p < 0.0001, UL + Static + VH vs. UL + Run + VH: p = 0.0017, UL + Static + AZD1480 vs. UL + Run + LPS: p < 0.0001, UL + Run + VH vs. UL + Run + LPS: p < 0.0001. One‐way ANOVA: F (3,36) = 8.139, p = 0.0003, Tukey's multiple comparisons test: UL + Static + VH vs. UL + Static + AZD1480: p = 0.0007, UL + Static + VH vs. UL + Run + VH: p = 0.0462, UL + Static + AZD1480 vs. UL + Run + LPS: p = 0.0023, n = 10/group in fear conditioning). * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001.

Article Snippet: At 2 weeks after UL induction, mice received daily oral gavage of either AZD1480 (HY‐10193, MCE) at 25 mg/kg or a vehicle (VH) control consisting of 0.1% dimethyl sulfoxide (DMSO; HY‐Y0320, MCE) [ ].

Techniques:

Journal: CNS Neuroscience & Therapeutics

Article Title: Aerobic Exercise Promotes Hippocampal Neurogenesis and Ameliorates Cognitive Dysfunction Induced by Unilateral Labyrinthectomy

doi: 10.1002/cns.70773

Figure Lengend Snippet: AZD1480 rescues the UL‐mediated suppression of hippocampal neurogenesis, while LPS markedly attenuates the pro‐proliferative effects of running. (A) Representative images showing BrdU+ and DAPI+ cells in the DG. (B) AZD1480 increases the number of BrdU+ cells induced by UL, while LPS counteracts the neuroproliferative effects induced by running. (One‐way ANOVA: F (3,36) = 21.29, p < 0.0001, Tukey's multiple comparisons test: UL + Static + VH vs. UL + Static + AZD1480: p = 0.0001, UL + Static + VH vs. UL + Run + VH: p < 0.0001, UL + Static + AZD1480 vs. UL + Run + LPS: p = 0.0094, UL + Run + VH vs. UL + Run + LPS: p < 0.0001). (C) Representative images showing Ki67+ and DAPI+ cells in the DG. (D) Running increases the number of UL‐induced Ki67+ cells, while AZD1480 and LPS have no significant effect on Ki67+ cell counts. (One‐way ANOVA: F (3,36) = 4.058, p = 0.0139, Tukey's multiple comparisons test: UL + Static + VH vs. UL + Run + VH: p = 0.0092). (E) Representative images showing DCX+ and DAPI+ cells in the DG. (F) AZD1480 increases the number of DCX+ cells induced by UL, while LPS counteracts the neuroproliferative effects induced by running. (One‐way ANOVA: F (3,36) = 10.35, p < 0.0001, Tukey's multiple comparisons test: UL + Static + VH vs. UL + Static + AZD1480: p = 0.0007, UL + Static + VH vs. UL + Run + VH: p < 0.0001, UL + Run + VH vs. UL + Run + LPS: p = 0.0490). (G) Representative photomicrographs of the dendritic branches of GFP+ cells in the DG. GFP+ cells were labeled with retrovirus pROVEF1a‐EGFP, which was injected in the DG. (H) AZD1480 significantly increases the total number of dendritic branches in individual GFP + newborn neurons induced by UL. (One‐way ANOVA: F (3,28) = 12.20, p < 0.0001, Tukey's multiple comparisons test: UL + Static + VH vs. UL + Static + AZD1480: p = 0.0012, UL + Static + VH vs. UL + Run + VH < 0.0001, UL + Static + VH vs. UL + RUN + LPS: p = 0.0020).

Article Snippet: At 2 weeks after UL induction, mice received daily oral gavage of either AZD1480 (HY‐10193, MCE) at 25 mg/kg or a vehicle (VH) control consisting of 0.1% dimethyl sulfoxide (DMSO; HY‐Y0320, MCE) [ ].

Techniques: Labeling, Injection

Journal: bioRxiv

Article Title: Anticipating on-target resistance to WRN inhibitors in microsatellite unstable cancers

doi: 10.64898/2026.01.22.700152

Figure Lengend Snippet: ( A ) Analysis of cell-line dependency on WRN and susceptibility to HRO761, stratified by MSI status; MSS: microsatellite stable; NA: non-applicable ( Table S3 ). ( B ) Clonogenic assays on a representative panel of MSI-high and MSS/MSI-low cell lines in response to HRO761 (1 μM). The X axis represents the surviving fraction compared to the DSMO control counts. ( C ) Schematic of the genome-wide synthetic lethality screen design. ( D ) Representation of NormZ values per gene generated using DrugZ, comparing DMSO-treated versus HRO761-treated RKO cell populations. ( E ) Survival curves of RKO cells transduced with sgRNAs targeting PPM1D (left) and DCLRE1C (right) using a one-vector system. Six days post-infection, cells were exposed to HRO761 for 7 days, and confluency was measured by total DAPI intensity. Mean ± s.e.m. compared to DMSO-treated control cells. N = 4; except DCLRE1C_1, N = 2. (F) ZIP synergy scores derived for the combination of HRO761 with either GSK-2830371 (WIP1i) or AZD-7648 (DNA-PKi) in RKO using the matrix datasets in Fig. S3D. Mean for N = 2 ( G ) Survival analysis of RKO cells treated with either HRO761 (WRNi) at 179 nM, GSK-2830371 (WIP1i) at 5 μM or both (combo) for 7 days. Confluency was measured with Incucyte. Relative survival is calculated with respect to a DMSO-treated control. Mean ± SD for N = 2. ( H ) Survival analysis of RKO cells treated with either HRO761 at 89 nM, AZD-7648 (DNA-PKi) at 1.78 μM or both for 7 days, as in ( G ). Mean ± SD for N = 2. ( I ) ZIP synergy scores derived for the combination of HRO761 with either GSK-2830371 (WIP1i) or AZD-7648 (DNA-PKi) in HCT116 cells. Mean for N = 2 ( J ) Survival analysis of HCT116 cells treated with either HRO761 at 70 nM, GSK-2830371 at 1.6 μM or both; HRO761 at 45 nM, AZD-7648 (DNA-PKi) at 6.45 μM or both for 7 days. Mean ± SD for N = 2.

Article Snippet: GSK-2830371 and AZD-7648 were acquired from MedChemExpress.

Techniques: Control, Genome Wide, Generated, Transduction, Plasmid Preparation, Infection, Derivative Assay