Neurogenic differentiation factor NeuroD confers protection against radiation-induced intestinal injury in mice.

Han Cao,Ming Chen,Chun-Gen Xing,Shuyu Zhang,Ming Li,Xiao-Dong Yang,Wei Zhu,Yanchao Ma,Jianping Cao,Chao Yang,Jing Xu,Aonan Du

doi:10.1038/srep30180

Abstract

The gastrointestinal tract, especially the small intestine, is particularly sensitive to radiation, and is prone to radiation-induced injury as a result. Neurogenic differentiation factor (NeuroD) is an evolutionarily-conserved basic helix-loop-helix (bHLH) transcription factor. NeuroD contains a protein transduction domain (PTD), which allows it to be exogenously delivered across the membrane of mammalian cells, whereupon its transcription activity can be unleashed. Whether NeuroD has therapeutic effects for radiation-induced injury remains unclear. In the present study, we prepared a NeuroD-EGFP recombinant protein, and explored its protective effects on the survival and intestinal damage induced by ionizing radiation. Our results showed that NeuroD-EGFP could be transduced into small intestine epithelial cells and tissues. NeuroD-EGFP administration significantly increased overall survival of mice exposed to lethal total body irradiation (TBI). This recombinant NeuroD also reduced radiation-induced intestinal mucosal injury and apoptosis, and improved crypt survival. Expression profiling of NeuroD-EGFP-treated mice revealed upregulation of tissue inhibitor of metalloproteinase 1 (TIMP-1), a known inhibitor of apoptosis in mammalian cells. In conclusion, NeuroD confers protection against radiation-induced intestinal injury, and provides a novel therapeutic clinical option for the prevention of intestinal side effects of radiotherapy and the treatment of victims of incidental exposure.

Highlights

The application of radiation and radioactive compounds in agricultural and medical technologies have afforded enormous benefits to humankind, but overexposure to the ionizing radiation can cause acute radiation syndrome (ARS), posing a complex medical challenge[1]
Our results showed that neurogenic differentiation factor (NeuroD)-EGFP administration significantly increased the overall survival of mice exposed to lethal total-body irradiation (TBI) and ameliorated radiation-induced intestinal mucosal injury by upregulating anti-apoptotic tissue inhibitor of metalloproteinase 1 (TIMP-1)
NeuroD expression is altered in response to radiation, C57BL/6J mice were exposed to different doses of TBI, whereupon the small intestines were collected and the expression of NeuroD was determined 6 h after irradiation

Summary

Introduction

The application of radiation and radioactive compounds in agricultural and medical technologies have afforded enormous benefits to humankind, but overexposure to the ionizing radiation can cause acute radiation syndrome (ARS), posing a complex medical challenge[1]. A combination of pentoxifylline and tocopherol has demonstrated potential as radioprotectors or radiomitigators[3] These radioprotective drugs may induce severe side effects in patients, limiting their application. Exploring the molecular events of ARS, and developing effective therapeutic treatments, is urgently needed to improve the outcomes of radiation-induced injuries. There are no effective clinical treatments for radiation-induced intestinal injury. Our previous research demonstrated that supplementation of exogenous NeuroD protein can be transduced into the small intestine epithelium cells post intraperitoneal injection, thereby alleviating the symptoms of diabetes mellitus within a mouse model induced by enteric expression of insulin[18]. Our results showed that NeuroD-EGFP administration significantly increased the overall survival of mice exposed to lethal total-body irradiation (TBI) and ameliorated radiation-induced intestinal mucosal injury by upregulating anti-apoptotic tissue inhibitor of metalloproteinase 1 (TIMP-1)

Methods

Results

Conclusion