当归补血汤干预NRF2-Notch信号调控辐射旁效应“毒损髓络”的机制研究
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摘要
目的探讨当归补血汤干预NRF2-Notch信号调控辐射旁效应"毒损髓络"的机制。方法将72只BALB/c小鼠随机分成正常对照组,全身辐射组,半身辐射组,给药1、2、3组。4Gy137Cs-γ射线照射辐射各组小鼠,除全身辐射组外均仅照射小鼠上半身,给药各组并用不同剂量的当归补血汤灌胃1周,处死小鼠取脾和骨髓。观察各组小鼠生存状态改变,并检测体重和脾指数的变化;cck8法检测骨髓细胞的增殖活力;realtime RT-PCR、Western-blot技术检测小鼠骨髓的NRF2-Notch通路相关基因蛋白的表达变化。结果同正常对照组相比:仅辐射各组小鼠生存状态明显弱于给药各组,小鼠骨髓细胞增殖活力降低(P<0.05);骨髓细胞NRF2、Notch1、Jagged1及PCNA基因mRNA表达下调(P<0.05);骨髓细胞Jagged1、HES1及PCNA蛋白表达下调,全身辐射组尤为明显。服药1周后,除给药1组外,给药各组骨髓细胞活力增加(P<0.05),且具有剂量依赖性;骨髓细胞NRF2 mRNA表达增加,激活Notch通路,其下游节点基因HES1表达上调(P<0.05),靶基因PCNA表达增加(P<0.05);骨髓细胞Jagged1、HES1及PCNA蛋白表达量均增加,且具有剂量依赖性,实验各组小鼠骨髓细胞Cleaved Notch1的表达成阴性。结论当归补血汤可能通过上调NRF2基因的表达,激活Notch通路,促进辐射小鼠骨髓细胞的增殖分化,缓解电离辐射靶效应或旁效应造成的骨髓抑制,促进造血免疫系统重建。
引文
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[6]Jung H,Kim MJ,Kim DO,et al.TXNIP maintains the hematopoietic cell pool by switching the function of p53 under oxidative stress[J].Cell Metab,2013,18(1):75.
[7]Kim JH,Thimmulappa RK,Kumar,et al.NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation[J].J Clin Invest,2014,124(2):730.
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