Abstract
The pathological mechanisms of radiation ulcer remain unsolved and there is currently no effective medicine. Here, we demonstrate that persistent DNA damage foci and cell senescence are involved in radiation ulcer development. Further more, we identify cordycepin, a natural nucleoside analogue, as a potent drug to block radiation ulcer (skin, intestine, tongue) in rats/mice by preventing cell senescence through the increase of NRF2 nuclear expression (the assay used is mainly on skin). Finally, cordycepin is also revealed to activate AMPK by binding with the α1 and γ1 subunit near the autoinhibitory domain of AMPK, then promotes p62-dependent autophagic degradation of Keap1, to induce NRF2 dissociate from Keap1 and translocate to the nucleus. Taken together, our findings identify cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents, and activation of AMPK or NRF2 may thus represent therapeutic targets for preventing cell senescence and radiation ulcer.
Highlights
The pathological mechanisms of radiation ulcer remain unsolved and there is currently no effective medicine
We demonstrate that persistent DNA damage foci forms and senescent cells accumulate in radiation ulcer, which are involved in the development of radiation ulcer
In order to identify the relationship between cell senescence and radiation ulcer, a rat skin ulcer model upon high radiation dose (40 Gy) exposure was established[15], which would result in aggravating erythema, desquamation, and ulceration of the skin (Fig. 1a)
Summary
The pathological mechanisms of radiation ulcer remain unsolved and there is currently no effective medicine. We demonstrate that persistent DNA damage foci and cell senescence are involved in radiation ulcer development. Radiation therapy technology has progressed substantially, patients still suffer from various degrees of non-specific radiation damage to non-cancerous tissues. These chronic wounds can last for several years and cause great distress to patients[4,5,6]. The pathological mechanisms of radiation ulcer remain unsolved and there is no effective medicine[4]. It has been proposed that radiation is a significant contributing factor to DNA damage and cell senescence, which coincide with life-long delayed repair and regeneration of irradiated tissues[7,8,9]
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