Psoralidin, a dual inhibitor of COX‐2 and 5‐LOX, regulates ionizing radiation (IR)‐induced pulmonary inflammation

Abstract

Radiotherapy is the most significant non‐surgical cancer treatment, however it is restricted by two major problems: radioresistance and normal tissue damage. We focused on radiation‐induced normal cell damage, and are concerned with inflammation as a main limiting factor in the radiotherapy. Psoralidin, a coumestan derivative isolated from the seed of Psoralea corylifolia, has been studied for various biological properties. However, little is known regarding its effects on IR‐induced pulmonary inflammation. The aim of this study is to investigate mechanisms of IR‐induced inflammation and to examine therapeutic mechanisms of psoralidin. We demonstrated that IR‐induced ROS activated COX‐2 and 5‐LOX pathway in HFL‐1 and MRC‐5 cells. Psoralidin inhibited the IR‐induced COX‐2 expression and PGE2 production through regulation of PI3K/Akt and NF‐κB signaling. Also, psoralidin blocked IR‐induced LTB4 production through a direct interaction of psoralidin and FLAP. IR‐induced fibroblast migration was notably attenuated by psoralidin. Moreover, psoralidin suppressed IR‐induced expression of pro‐inflammatory cytokines and ICAM‐1 in vivo. Taken together, our findings reveal a regulatory mechanism of IR‐induced pulmonary inflammation in human normal lung fibroblast and mice, and suggest that psoralidin may be useful as a potential radiopreventive agent against radiation‐induced normal tissue injury.

Metabolic Phenotyping Reveals a Lipid Mediator Response to Ionizing Radiation

“…Significantly, it is reported that ionizing radiation activates COX and LOX pathways and that nonsteroidal anti-inflammatory drug treatment reduces radiation-induced expression of pro-inflammatory cytokines (e.g., TNF-α, TGF-β, IL-6, and IL-1 α/β). − In agreement with these observations, our results further suggest that oxylipins-mediated inflammation might be a critical signaling step for the organism response to radiation. Macrophage activation leading to a persistent inflammatory response has been described in radiation therapy for cancer ,, in animals following irradiation and in atomic bomb survivors. , Like other inflammatory cytokines, oxylipins are major components of immediate-early gene programs.…”

“…As such, they can be rapidly activated after tissue irradiation as part of the immune response to stress factors and thus they might disrupt cellular homeostasis over time, causing detrimental health effects . It is therefore reasonable to speculate that oxylipins-mediated inflammation could be involved in the bystander and abscopal effects associated with clinical exposures to ionizing radiation in a radiotherapy-type situation. ,,− …”

Opportunities and Challenges for Fatty Acid Mimetics in Drug Discovery

“…In contrast, 2 binds to the hydrophobic subpocket and displays enthalpy-driven binding. 76 It is well precedented in medicinal chemistry that occupation of hydrophobic binding sites is highly favorable for a ligand's binding potency. 77 However, the underlying effects are diverse, and a global interpretation of effects contributing to binding is not unambiguous.…”

Fruits and their phytochemicals in mitigating the ill effects of ionizing radiation: review on the existing scientific evidence and way forward

“…194 Additionally, psoralidin, a coumestan isolated from the seed, effectively mitigates IR-induced pulmonary inflammation in cultured human normal lung fibroblasts, MRC-5 and HFL-1 in vitro. 195 Compared to the radiation alone cohorts, treatment of MRC-5 and HFL-1 cells mitigated the IR-induced fibroblast migration. They inhibited the radiation-induced increase in the expression of COX-2 and PGE (2) production by modulating the PI3K/Akt and NF-κB pathways.…”