Speaker
Description
The hematopoietic system's high sensitivity to ionizing radiation poses a critical risk of infection, bleeding, and mortality. Blood cell counts can significantly drop within hours after exposure to radiation, yet effective pharmacotherapy options remain scarce. Nitro-derivatives of fatty acids (NO2-FAs) offer promising properties, including anti-oxidative, anti-inflammatory, cytoprotective, and immunomodulatory effects. They also play roles in regulating cell cycle, proliferation, and activating NRF2, a key regulator of cellular responses to oxidative stress. This study investigated the impact of NO2-FAs on NRF2 expression (via western blot) and the expression of NRF2-responsive genes (via PCR) and proteins (via western blot) in bone marrow cells in vitro. Additionally, we explored the effects of NO2-FAs on hematopoiesis (through colony-forming units), cytokine release (via ELISA), and survival rates of irradiated (Cobalt-60) mice in vivo. The NO2-FA derivatives 10-NO2OA and 9-NO2OA were found to increase the expression of NRF2 and its responsive genes more than the other tested molecules. Similarly, the expression of HO-1 and GCLM proteins were increased. Notably, the mixed 9/10-NO2OA isomer significantly boosted bone marrow cellularity, including granulocyte-macrophage colony-forming cells and erythroid progenitors, three days post-total body sub-lethal irradiation (4 Gy). Furthermore, 9/10-NO2OA facilitated the recovery of white blood cells (lymphocytes, neutrophils, and monocytes) in the peripheral blood seven days following radiation exposure (4 Gy), potentially due to induced production of granulocyte colony-stimulating factor post-irradiation. Importantly, 10-NO2OA improved survival rates in lethally irradiated (7.5 Gy) mice. In summary, our results demonstrate that NO2-FAs offer significant protection to hematopoiesis following radiation exposure, highlighting their potential as effective agents in medical radiation countermeasures. This research was supported by the GAČR grant 23-06051S.
