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Xin-Yue Yang,1,* Lina Geng,2,* Ronghui Li,2 Ji-Xian Song,1 Cui-Ling Jia,1 Ji-Ren An,1,3 Meng-Fan Sun,1 Shan Xu,1 Ya-Jing Guo,1 Yashuo Zhao,1 En-Sheng Ji1 1Hebei Technology Innovation Center of TCM Combined Hydrogen Medicine, Hebei University of Chinese Medicine, Shijiazhuang, People’s Republic of China; 2College of Chemistry and Material Science, Hebei Normal University, Shijiazhuang, People’s Republic of China; 3The First Clinical College, Liaoning University of Traditional Chinese Medicine, Shenyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yashuo Zhao; En-Sheng Ji, No. 3, Luqian Xingyuan Road, Shijiazhuang, 050200, People’s Republic of China, Email zys870207@126.com; jesphy@126.comBackground: Chronic intermittent hypoxia (CIH) could cause neuronal damage, accelerating the progression of dementia. However, safe and effective therapeutic drugs and delivery are needed for successful CIH therapy.Purpose: To investigate the neuroprotective effect of Huperzine A (HuA) packaged with nanoliposomes (HuA-LIP) on neuronal damage induced by CIH.Methods: The stability and release of HuA-LIP in vitro were identified. Mice were randomly divided into the Control, CIH, HuA-LIP, and HuA groups. The mice in the HuA and HuA-LIP groups received HuA (0.1 mg/kg, i.p.), and HuA-LIP was administered during CIH exposure for 21 days. HuA-LIP contains the equivalent content of HuA.Results: We prepared a novel formulation of HuA-LIP that had good stability and controlled release. First, HuA-LIP significantly ameliorated cognitive dysfunction and neuronal damage in CIH mice. Second, HuA-LIP elevated T-SOD and GSH-Px abilities and decreased MDA content to resist oxidative stress damage induced by CIH. Furthermore, HuA-LIP reduced brain iron levels by downregulating TfR1, hepcidin, and FTL expression. In addition, HuA-LIP activated the PKAα/Erk/CREB/BDNF signaling pathway and elevated MAP2, PSD95, and synaptophysin to improve synaptic plasticity. Most importantly, compared with HuA, HuA-LIP showed a superior performance against neuronal damage induced by CIH.Conclusion: HuA-LIP has a good sustained-release effect and targeting ability and efficiently protects against neural injury caused by CIH.Keywords: huperzine A, nanoliposomes, neuronal damage, chronic intermittent hypoxia, Iron

Our previous study found that ferric citrate-loaded liposome (FAC-LIP) exhibited stable physical characteristics and have better efficacy to treat anemia of inflammation (AI) than free ferric citrate (FAC). This study was aimed at oral pharmacokinetics of both FAC-LIP and FAC in Sprague Dawley (SD) rats. Results showed that the main pharmacokinetic parameters of FAC-LIP in vivo were as follows: Cmax of 445.89 ± 23.56 μg/mL, Tmax of 4 h, t1/2 of 13.01 ± 2.04 h, MRT of 20.54 ± 2.06 h and AUC0-24 h of 6446.1 ± 516.58 hμg/mL. The relative bioavailability of FAC-LIP formulation was 215.7%, nearly 2-fold in comparison with free FAC formulation. FAC-LIP showed a sustained-release effect, a wide absorption and a complete elimination. These results support the fact that FAC-LIP has the potential of improving oral bioavailability and reducing iron accumulation in liver, which could influence the available iron level in the blood system. FAC-LIP could be used as an effective iron supplement.

The stress-inducible immediate early response gene X-1 (IEX-1) regulates cell proliferation and apoptosis in a cell type and stimulus-dependent manner. The aim of this study was to investigate IEX-1 expression in preeclampsia placenta and human umbilical vein endothelial cells (HUVECs) cultured in the serum isolated from preeclampsia patients, to explore its relationship with the pathogenesis of preeclampsia. Thirty preeclampsia patients with 10 cases in the moderate group, 20 cases in the severe group (PE group) and 20 cases of normal pregnant women (control group) were randomly obtained. Reverse transcriptase-polymerase chain reaction and immunohistochemistry showed that IEX-1 expression was significantly higher in preeclampsia patients than in normal pregnant women (p 0.05). There was also a significant difference between moderate and severe preeclampsia (p 0.05). IEX-1 protein was mainly present in cytoplasm of placental trophoblast cells and decidual cells. Compared with the normal pregnancy group, IEX-1 in the preeclampsia group was colored more obviously, and the color was strengthened in correlation with the severity of the disease using immunocytochemial method. Flow cytometry and MTT revealed that the serum isolated from preeclampsia patients appeared to promote IEX-1 expression in cytoplasm of HUVECs, inhibited the proliferation and promoted the apoptosis of HUVECs when compared to the serum of normal pregnant women. Our study demonstrates a correlation of IEX-1 expression levels with the severity of preeclampsia. Given a well-known function of IEX-1 in regulation of apoptosis, IEX-1 may be important in the pathogenesis of preeclampsia by regulating placental villous trophoblast and decidual cell apoptosis as well as participation in endothelial cell injury process.