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Autophagy and apoptosis have been known to be interconnected positively or negatively; however, the molecular mechanisms mediating these two cellular processes are not fully understood. In the present study, we demonstrated that the exposure of L929 cells to oridonin led to intracellular reactive oxygen species generation, followed by lipid peroxidation, as well as decreases in superoxide dismutase and glutathione activities. The reactive oxygen species scavenger N-acetyl-cysteine resulted in the complete inhibition of oridonin-induced apoptosis and mitochondrial membrane potential collapse. We showed that reactive oxygen species triggered apoptosis by Bax translocation, cytochrome c release and extracellular signalregulated kinase activation. Further data confirmed that oridonin also induced L929 cell autophagy, as demonstrated by extensive autophagic vacuolization and the punctuate distribution of monodansylcadaverine staining and GFP-LC3, as well as the LC3-II ⁄ LC3-I proportion and Beclin 1 activation. Subsequently, we found that inhibition of autophagy by 3-methyladenine or small interfering RNA against LC3 and Beclin 1 promoted oridonin-induced cell apoptosis. The effects of p38 and nuclear factorkappa B in oridonin-induced apoptosis and autophagy were further examined. Interruption of p38 and nuclear factor-kappa B activation by specific inhibitors or small interfering RNAs promoted apoptosis and reactive oxygen species generation, but decreased autophagy. Moreover, we showed that inhibition of autophagy reduced oridonin-induced activation of p38. Additionally, nuclear factor-kappa B activation was inhibited by blocking the p38 pathway. Consequently, these findings indicate that oridonininduced L929 cell apoptosis is regulated by reactive oxygen species-mediated signaling pathways, and that oridonin-induced autophagy may block apoptosis by up-regulating p38 and nuclear factor-kappa B activation.

Janus nanoparticles with an anisotropic feature concentrated multiple properties on a single carrier, providing synergistic effects. In this study, dual-functionalized Janus nanoparticles (HA-JMSN/DOX-DMMA) were constructed with a tumor-targeting ligand (hyaluronic acid, HA) modified on the one side and a charge reversal group (2,3-dimethylmaleic anhydride, DMMA) on the other side. The drug release of HA-JMSN/DOX-DMMA was positively correlated with the acidity of the environment. The cytotoxicity and cell uptake of HA-JMSN/DOX-DMMA were superior to the isotropous nanoparticles. The endocytosis pathway of HA-JMSN/DOX-DMMA involved the clathrin-mediated endocytosis (HA) and the micropinocytosis (DMMA) at the same time, which indicated that they both participated in the interaction between nanoparticles and tumor cells. After being injected intravenously in mice, the distribution of HA-JMSN/DOX-DMMA in tumor was enhanced significantly. The antitumor therapy study in vivo showed that HA-JMSN/DOX-DMMA inhibited tumor growth and improved the survival rate of tumor-bearing mice effectively. In general, HA-JMSN/DOX-DMMA could take the synergistic effect of active targeting and charge reversal to deliver drug in tumor cells and kill them efficiently, which was a promising antitumor nanodrug.

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