Inhibition of autophagy protects against PAMAM dendrimers-induced hepatotoxicity
Inhibition of autophagy protects against PAMAM dendrimers-induced hepatotoxicity
复制标题
DOI：
10.3109/17435390.2014.930533
复制
发表时间：
2015-05-01
期刊：
影响因子：
5
通讯作者：
Ju, Dianwen
中科院分区：
文献类型：
--
作者：
Li, Yubin;Zeng, Xian;Ju, Dianwen
纳米材料的毒性是其医学应用的最大挑战之一。虽然纳米材料的毒性已被广泛报道，但其确切的毒性机制仍然没有得到很好的阐明。因此，减少纳米材料毒性的方法的探索是有限的。在这项研究中，我们报道了聚酰胺胺（PAMAM）树枝状聚合物，一种广泛用于制药工业的纳米材料，通过诱导细胞生长抑制，线粒体损伤和凋亡引起人类肝细胞的毒性。同时，自噬在PAMAM树枝状聚合物诱导的肝细胞毒性和抑制自噬挽救的肝细胞活力中被激活，表明自噬在PAMAM树枝状聚合物诱导的肝毒性中起关键作用。为了进一步探索减弱PAMAM树枝状聚合物诱导的肝损伤的方法，在体内模型中研究了自噬抑制剂对PAMAM树枝状聚合物的肝毒性的影响。PAMAM树枝状聚合物给药小鼠的自噬阻断导致体重恢复，肝组织损伤逆转，并保护血清生化参数的变化。此外，Akt/mTOR的抑制和Erk 1/2信号通路的激活参与PAMAM树状聚合物诱导的自噬。总的来说，这些发现表明自噬与PAMAM树状聚合物诱导的肝毒性相关，并支持自噬抑制剂可用于降低PAMAM树状聚合物的肝毒性的可能性。
Toxicity of nanomaterials is one of the biggest challenges in their medicinal applications. Although toxicities of nanomaterials have been widely reported, the exact mechanisms of toxicities are still not well elucidated. Consequently, the exploration of approaches to attenuate toxicities of nanomaterials is limited. In this study, we reported that poly-amidoamine (PAMAM) dendrimers, a widely used nanomaterial in the pharmaceutical industry, caused toxicity of human liver cells by inducing cell growth inhibition, mitochondria damage, and apoptosis. Meanwhile, autophagy was activated in PAMAM dendrimers-induced toxicity and inhibition of autophagy-rescued viability of hepatic cells, indicating that autophagy played a key role in PAMAM dendriemrs-induced hepatotoxicity. To further explore approaches to attenuate PAMAM dendrimers-induced liver injury, effects of autophagic inhibitors on PAMAM dendrimers' hepatotoxicity were investigated in an in vivo model. Autophagy blockage in PAMAM dendrimers-administered mice led to weight restoration, damage reversion of liver tissue, and protection against changes of serum biochemistry parameters. Moreover, inhibition of Akt/mTOR and activation of Erk1/2 signaling pathways were involved in PAMAM dendrimers-induced autophagy. Collectively, these findings indicated that autophagy was associated with PAMAM dendrimers-induced hepatotoxicity, and supported the possibility that autophagy inhibitors could be used to reduce hepatotoxicity of PAMAM dendrimers.