Li Danni,Liu Shaogang,Zhu Jiahao,Shen Liqun,Zhang Qi ying,Zhu Hua
Background The development of novel and effective drugs for targeted human hepatocellular carcinoma still remains a great challenge. The alkaloid nitidine chloride (NC), a component of a traditional Chinese medicine, has been shown to have anticancer properties, but doses at therapeutic levels have unacceptable side effects. Here we investigate folic acid modified D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS-FA) as a potential carrier for controlled delivery of the drug. Methods Synthesized TPGS-FA was characterized by FTIR, UV-visible and 1 H NMR spectroscopy, and TPGS loaded with NC was evaluated for its ability to induce apoptosis in Huh7 cells by Annexin V/PI and MTT assays, and observed by laser scanning confocal microscopy and inverted phase contrast microscopy. Results TPGS-FA/NC complexes were prepared successfully, and were homogenious with a uniform size of ~ 14 nm diameter. NC was released from the TPGS-FA/NC complexes in a controlled and sustained manner under physiological conditions (pH 7.4). Furthermore, its cytotoxicity to hepatocarcinoma cells was greater than that of free NC. Conclusions TPGS-FA is shown to be useful carrier for drugs such as NC, and TPGS-FA/NC could potentially be a potent and safe drug for the treatment of hepatocellular carcinoma.
Japanese encephalitis virus (JEV) is a typical mosquito-borne flavivirus that can cause central nervous system diseases in humans and animals. Host factors attempt to limit virus replication when the viruses invade the host by using various strategies for replication. It is essential to clarify the host factors that affect the life cycle of JEV and explore its underlying mechanism. Here, we found that USP1-associated factor 1 (UAF1; also known as WD repeat-containing protein 48) modulated JEV replication. We found that JEV propagation significantly increased in UAF1-depleted Huh7 cells. Moreover, we found that knockdown of UAF1 activated cell autophagic flux in further functional analysis. Subsequently, we demonstrated that autophagy can be induced by JEV, which promotes viral replication by inhibiting interferon-stimulated gene (ISG) expression in Huh7 cells. The knockdown of UAF1 reduced ISG expression during JEV infection. To explore the possible roles of autophagy in UAF1-mediated inhibition of JEV propagation, we knocked out ATG7 to generate autophagy-deficient cells and found that depletion of UAF1 failed to promote JEV replication in ATG7 knockout cells. Moreover, in ATG7-deficient Huh7 cells, interference with UAF1 expression did not lead to the induction of autophagy. Taken together, these findings indicate that UAF1 is a critical regulator of autophagy and reveal a mechanism by which UAF1 knockdown activates autophagy to promote JEV replication.IMPORTANCE Host factors play an essential role in virus replication and pathogenesis. Although UAF1 is well known to form complexes with ubiquitin-specific proteases, little is known about the function of the UAF1 protein itself. In this study, we confirmed that UAF1 is involved in JEV replication. Notably, we discovered a novel function for UAF1 in regulating autophagy. Furthermore, we demonstrated that UAF1 modulated JEV replication through its autophagy regulation. This study is the first description of the novel function of UAF1 in regulating autophagy, and it clarifies the underlying mechanism of the antiviral effect of UAF1 against JEV. These results provide a new mechanistic insight into the functional annotation of UAF1 and provide a potential target for increasing virus production during vaccine production.
This paper reports the antitumor activity and possible mechanism of anthraquinone derivatives containing substituted bisbenzyloxy groups. Series of anthraquinone derivatives containing substituted bisbenzyloxy groups were designed and synthesized by etherification and esterification. The antitumor activities of the synthesized substituted bisbenzyloxy anthraquinone derivatives on liver cancer cell Huh7, triple negative breast cancer cell line MDA-MB-231 and lung cancer cell A549 were in the order of methoxy substitution > methyl substitution > chloral substitution. Among these, the Compound KA-MO-g showed strong antitumor activity, especially against liver cancer Huh7 cells. Further studies on the antitumor mechanism showed that the Compound KA-MO-g simultaneously activated three pathways of endoplasmic reticulum stress (ERS), also caused impairment of endoplasmic reticulum (ER) functions, such as glycoprotein synthesis and disulfide bond formation are impeded and caused calcium overload,then increased mitochondrial ROS, damaged of mitochondria, changed of apoptosis-related protein levels, activated Caspase 3, induced the apoptosis of Huh7 cells. Because KA-MO-g showed strong antitumor activity, it is expected to be a new candidate drug for treating liver cancer and is worth further study.
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