Hao Yuhui, Liu Cong, Huang Jiawei, Gu Ying, Li Hong, Yang Zhangyou, Liu Jing, Wang Weidong, Li Rong
State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038, China.
Department of Radiation Oncology, Shanghai Jiao Tong University Affiliated Sixth People Hospital, Shanghai 200233, PR China.
Toxicol Appl Pharmacol. 2016 Jan 1;290:116-25. doi: 10.1016/j.taap.2015.10.022. Epub 2015 Oct 31.
Depleted uranium (DU) mainly accumulates in the bone over the long term. Osteoblast cells are responsible for the formation of bone, and they are sensitive to DU damage. However, studies investigating methods of reducing DU damage in osteoblasts are rarely reported. Ghrelin is a stomach hormone that stimulates growth hormones released from the hypothalamic-pituitary axis, and it is believed to play an important physiological role in bone metabolism. This study evaluates the impact of ghrelin on DU-induced apoptosis of the osteoblast MC3T3-E1 and investigates its underlying mechanisms. The results show that ghrelin relieved the intracellular oxidative stress induced by DU, eliminated reactive oxygen species (ROS) and reduced lipid peroxidation by increasing intracellular GSH levels; in addition, ghrelin effectively suppressed apoptosis, enhanced mitochondrial membrane potential, and inhibited cytochrome c release and caspase-3 activation after DU exposure. Moreover, ghrelin significantly reduced the expression of DU-induced phosphorylated p38-mitogen-activated protein kinase (MAPK). A specific inhibitor (SB203580) or specific siRNA of p38-MAPK could significantly suppress DU-induced apoptosis and related signals, whereas ROS production was not affected. In addition, ghrelin receptor inhibition could reduce the anti-apoptosis effect of ghrelin on DU and reverse the effect of ghrelin on intracellular ROS and p38-MAPK after DU exposure. These results suggest that ghrelin can suppress DU-induced apoptosis of MC3T3-E1 cells, reduce DU-induced oxidative stress by interacting with its receptor, and inhibit downstream p38-MAPK activation, thereby suppressing the mitochondrial-dependent apoptosis pathway.
长期来看，贫铀（DU）主要蓄积在骨骼中。成骨细胞负责骨骼的形成，且对DU损伤敏感。然而，关于减少成骨细胞中DU损伤方法的研究报道较少。胃饥饿素是一种能刺激下丘脑-垂体轴释放生长激素的胃激素，据信在骨代谢中发挥重要生理作用。本研究评估了胃饥饿素对DU诱导的成骨细胞MC3T3-E1凋亡的影响，并探究其潜在机制。结果表明，胃饥饿素减轻了DU诱导的细胞内氧化应激，通过提高细胞内谷胱甘肽（GSH）水平消除了活性氧（ROS）并减少了脂质过氧化；此外，胃饥饿素有效抑制了凋亡，增强了线粒体膜电位，并在DU暴露后抑制了细胞色素c释放和半胱天冬酶-3激活。此外，胃饥饿素显著降低了DU诱导的磷酸化p38丝裂原活化蛋白激酶（MAPK）的表达。p38-MAPK的特异性抑制剂（SB203580）或特异性小干扰RNA（siRNA）可显著抑制DU诱导的凋亡及相关信号，而ROS产生不受影响。此外，抑制胃饥饿素受体可降低胃饥饿素对DU的抗凋亡作用，并逆转胃饥饿素对DU暴露后细胞内ROS和p38-MAPK的影响。这些结果表明，胃饥饿素可抑制DU诱导的MC3T3-E1细胞凋亡，通过与其受体相互作用减少DU诱导的氧化应激，并抑制下游p38-MAPK激活，从而抑制线粒体依赖性凋亡途径。
