The histone deacetylase inhibitor (HDAC), phenylbutyrate (PB), is a novel anti-tumor agent. Studies have demonstrated that HDAC inhibitors can suppress cutaneous radiation syndrome and stimulate hematopoiesis. The objective of this study was to test the ability of PB treatment to protect against acute gamma-radiation-induced lethality in the DBA/2 mouse model. A 30-day radiation lethality study was used to assess radioprotective capability of PB. Mechanisms were evaluated using western blots, flow cytometry, and the single-cell gel electrophoresis assay. Western blot studies showed that PB treatment acetylated histones in vivo. For radiation protection studies, prophylactic administration of PB (24 h preradiation; 1-50 mg/kg) provided radioprotection against gamma radiation (8-9.5 Gy) and PB demonstrated a DRF of 1.31 (P = 0.001; 95% confidence interval: 1.27, 1.36). When PB (10 mg/kg) was administered post-radiation (4 h), it also provided significant radioprotection at 8.0 Gy radiation (P = 0.022). PB treatment before radiation was associated with significant elevations in neutrophils and platelets following radiation. Results from single-cell gel electrophoresis of peripheral blood leukocytes demonstrated that PB treatment before radiation can attenuate DNA damage and inhibit radiation-induced apoptosis. These results indicate that an HDAC inhibitor like PB has potential as a radiation protector and that mechanisms of action include attenuation of DNA damage and inhibition of apoptosis.
Dysregulation of cholesterol homeostasis is associated with many diseases such as cardiovascular disease and cancer. Liver x receptors (LXRs) are major upstream regulators of cholesterol homeostasis and are activated by endogenous cholesterol metabolites such as 27-hydroxycholesterol (27HC). LXR and various LXR ligands such as 27HC have been described to influence several extra-hepatic biological systems. However, disparate reports of LXR function have emerged, especially with respect to immunology and cancer biology. This would suggest that similar to steroid nuclear receptors, the LXR can be selectively modulated by different ligands. Here, we use RNA-sequencing of macrophages and single-cell RNA-sequencing of immune cells from metastasis bearing murine lungs, to provide evidence that LXR satisfies the two principles of selective nuclear receptor modulation: (1) different LXR ligands result in overlapping but distinct gene expression profiles within the same cell type, and (2) the same LXR ligands differentially regulate gene expression in a highly context-specific manner, depending on the cell or tissue type. The concept that the LXR can be selectively modulated provides the foundation for developing precision-pharmacology LXR ligands that are tailored to promote those activities that are desirable (pro-immune), but at the same time minimizing harmful side effects (such as elevated triglyceride levels).
These results indicate that oral PB has potential as a radiation protector and a radiation mitigator and that potential mechanisms of action include attenuation of DNA damage, antioxidant activity, and bone marrow protection.
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