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Therapeutic Potential of NRF2 activating drug RTA-408 in suppressing T-cell effector responses and inflammatory bowel disease

ABSTRACT: Targeting T-cells has emerged as a promising therapeutic strategy for treating inflammatory diseases. Triterpenoids, classified as antioxidant inflammatory modulator (AIM) compounds, are known to influence immune cell functions. RTA-408 is an AIM drug that was approved last year for the treatment of neurological disorders. In this study, we demonstrate the anti-inflammatory effects of RTA-408, on both mouse and human T-cells. At picomolar concentrations, RTA-408 robustly induces NRF2 activation in T-cells and reduces T-cell activation, proliferation, and cytokine functions. In in vitro activated CD4 and CD8 T-cells isolated from mice and human blood, we observed a significant decrease in proliferation, and expression of inflammatory cytokine IFN-γ, and cytotoxic granules (perforin and granzyme B). Mechanistically, treatment with RTA-408 significantly suppressed glycolysis and mitochondrial respiration in human T-cells, while increasing the expression of pentose phosphate pathway genes, such as transketolase (TKT) and transaldolase (TALDO). These findings suggest that RTA-408 modulates T-cell metabolism. Furthermore, treatment of circulating T-cells from inflammatory bowel disease (IBD) patients with RTA-408 caused a reduction in expansion and the expression of the inflammatory cytokine IL-17. Our results highlight the therapeutic potential of RTA-408 in treating chronic inflammatory conditions like IBD by modulating T-cell activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277154 | GEO | 2025/04/01

REPOSITORIES: GEO

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Project description:Objective/Hypothesis: To assess the efficacy and mechanism of action of a novel approach to mitigate acute and chronic radiation toxicity in a validated animal model. We propose that synthetic triterpenoid RTA-408, an Nrf2 activator, activates additional protective pathways which stabilize soft tissue during radiation, thereby reducing necrosis and improves surgical outcomes in a subsequently created axial rotational flap. Methods: Experimental animal study utilizing Sprague-Dawley rats were divided into 3 cohorts: (i) radiation + DMSO (inert vehicle), (ii) radiation + RTA-408 (therapeutic drug), and (iii) no radiation + DMSO. Two main groups of rats were utilized in these experiments: (i) rotational flap experiment (n=40) and (ii) transcriptome analysis (n=9). In the first experiment all animals in the radiation cohorts underwent 40 Gy of radiation to the soft tissue of the abdomen. Then all three cohorts underwent surgery with construction of an inferior epigastric axial rotational flap, which was performed 30 days after resolution of acute injury from radiation in the radiation groups. Percentage of flap necrosis, the primary endpoint, was calculated by standardized measurement of tissue necrosis by blinded observers and vascular density measured by CD31 staining. In a second experiment, an additional three cohorts, with identical treatment as described above underwent serial punch biopsies of the abdominal skin before, during, and after radiation and drug/vehicle control treatment. Transcriptome analysis utilizing gene set enrichment analysis and digital PCR were performed at the various timepoints. Results: In the first experiment, 40 rats were divided into the three groups and underwent treatment accordingly. The average flap necrosis was 20% (95% CI, 16-45%) in the radiation control group, 3% (95% CI, 0-11%) in the non-irradiated control, and 3% (95% CI, 0.2-10%) in the radiation group treated with RTA-408. Vascular density was preserved in the treatment group as compared to the radiated control. Nine rats were included in the second experiment, and transcriptome analyses in the treatment group revealed robust activation of antioxidant pathways with induced expression of genes associated with hypoxia and adipogenesis/angiogenesis. Conclusions: Administration of RTA-408 during radiation treatment in a rat model resulted in transcriptome changes which appear to mitigate the toxic effects of radiation, preserving capillary networks and improving flap survival and tissue healing after subsequent surgery. Such reductions in toxicity may have broad implications for functional outcomes and salvage surgery following therapeutic irradiation.

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Therapeutic Potential of NRF2 activating drug RTA-408 in suppressing T-cell effector responses and inflammatory bowel disease

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