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Cheng M.,Pudong New Area District Zhoupu Hospital | Chen H.,Zhejiang Huafon Spandex Co | Wang Y.,Wuhan University of Technology | Xu H.,Fudan University | He B.,Fudan University
International Journal of Nanomedicine | Year: 2014

The nanoparticle drug delivery system, which uses natural or synthetic polymeric material as a carrier to deliver drugs to targeted tissues, has a broad prospect for clinical application for its targeting, slow-release, and biodegradable properties. Here, we used chitosan (CTS) and hepatoma cell-specific binding molecule glycyrrhetinic acid to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by infrared (IR) spectra and hydrogen-1 nuclear magnetic resonance. The GA-CTS/5-fluorouracil (5-FU) nanoparticles were synthesized by combining GA-CTS and 5-FU and conjugating 5-FU onto the GA-CTS nanomaterial. The central composite design was performed to optimize the preparation process as CTS:tripolyphosphate sodium (TPP) weight ratio =5:1, 5-FU:CTS weight ratio =1:1, TPP concentration =0.05% (w/v), and cross-link time =50 minutes. GA-CTS/5-FU nanoparticles had a mean particle size of 193.7 nm, a polydispersity index of 0.003, a zeta potential of +27.4 mV, and a drug loading of 1.56%. The GA-CTS/5-FU nanoparticle had a protective effect on the drug against plasma degrading enzyme, and provided a sustained release system comprising three distinct phases of quick, steady, and slow release. Our study showed that the peak time, half-life time, mean residence time and area under the curve of GA-CTS/5-FU were longer or more than those of the 5-FU group, but the maximum concentration (Cmax) was lower. We demonstrated that the nanoparticles accumulated in the liver and have significantly inhibited tumor growth in an orthotropic liver cancer mouse model. © 2014 Cheng et al.


Cheng M.,Pudong New Area District Zhoupu Hospital | Gao X.,Pudong New Area District Zhoupu Hospital | Wang Y.,Wuhan University of Technology | Chen H.,Zhejiang Huafon Spandex Co. | And 4 more authors.
International Journal of Nanomedicine | Year: 2013

Nanoparticle drug delivery systems using polymers hold promise for clinical applications. We synthesized dual-ligand modified chitosan (GCGA) nanoparticles using lactic acid, glycyrrhetinic acid, and chitosan to target the liver in our previous studies. We then synthesized the GCGA/5-FU nanoparticles by conjugating 5-fluorouracil (5-FU) onto the GCGA nanomaterial, which had a mean particle size of 239.9 nm, a polydispersity index of 0.040, a zeta potential of +21.2 mV, and a drug loading of 3.90%. GCGA/5-FU nanoparticles had good slow release properties, and the release process could be divided into five phases: small burst release, gentle release, second burst release, steady release, and slow release. Inhibitory effects of GCGA/5-FU on tumor cells targeted the liver, and were time and dose dependent. GCGA nanoparticles significantly prolonged the efficacy of 5-FU on tumor cells, and alleviated the resistance of tumor cells to 5-FU. GCGA/5-FU nanoparticles were mostly concentrated in the liver, indicating that the GCGA nanoparticles were liver targeting. GCGA/5-FU nanoparticles significantly suppressed tumor growth in orthotopic liver transplantation mouse model, and improved mouse survival. © 2013 Cheng et al.


PubMed | Zhejiang Huafon Spandex Co, Fudan University, Pudong New Area District Zhoupu Hospital and Wuhan University of Technology
Type: | Journal: International journal of nanomedicine | Year: 2014

The nanoparticle drug delivery system, which uses natural or synthetic polymeric material as a carrier to deliver drugs to targeted tissues, has a broad prospect for clinical application for its targeting, slow-release, and biodegradable properties. Here, we used chitosan (CTS) and hepatoma cell-specific binding molecule glycyrrhetinic acid to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by infrared (IR) spectra and hydrogen-1 nuclear magnetic resonance. The GA-CTS/5-fluorouracil (5-FU) nanoparticles were synthesized by combining GA-CTS and 5-FU and conjugating 5-FU onto the GA-CTS nanomaterial. The central composite design was performed to optimize the preparation process as CTS:tripolyphosphate sodium (TPP) weight ratio =5:1, 5-FU:CTS weight ratio =1:1, TPP concentration =0.05% (w/v), and cross-link time =50 minutes. GA-CTS/5-FU nanoparticles had a mean particle size of 193.7 nm, a polydispersity index of 0.003, a zeta potential of +27.4 mV, and a drug loading of 1.56%. The GA-CTS/5-FU nanoparticle had a protective effect on the drug against plasma degrading enzyme, and provided a sustained release system comprising three distinct phases of quick, steady, and slow release. Our study showed that the peak time, half-life time, mean residence time and area under the curve of GA-CTS/5-FU were longer or more than those of the 5-FU group, but the maximum concentration (C(max)) was lower. We demonstrated that the nanoparticles accumulated in the liver and have significantly inhibited tumor growth in an orthotropic liver cancer mouse model.


Lu Y.,Pudong New Area District Zhoupu Hospital | Wang L.,Shanghai JiaoTong University | Hao Y.,Shanghai JiaoTong University | Wang Z.,Pudong New Area District Zhoupu Hospital | And 2 more authors.
BMC Musculoskeletal Disorders | Year: 2013

Background: Multi-detector computed tomography (MDCT) was used in order to assess the trabecular distribution of proximal femur and its relationship with hip fragility fractures. Methods. A total of 99 elderly women were scanned by MDCT including: 27 trochanteric hip fractures (group A), 40 femoral neck fractures (group B), and 32 non-fractures (group C). A mid-coronal MPR image of the proximal femur was reconstructed for every patient by e-Film95 software. Four regions of interest (ROI) were chosen in the images including compressive trabecula (ComT), tensile trabecula (TenT), trochanteric trabecula (TroT) and Ward's triangle (WT) region. The mean CT values were measured by the software. Results: The mean age was 81.44, 74.10 and 69.25 years for groups A, B and C, respectively. There was significant inter-group differences based on one-way ANOVA (P<0.05). The CT values in the four ROIs had significant differences in the groups except for TenT between group A and B (P>0.05). After the age adjustment with ANCOVA, the mean CT values of TroT and WT were significantly lower in group A as compared to that of the group B (P<0.05). However, there were no significant differences for ComT and TenT between groups A and B (P>0.05). Conclusions: The occurrence of femoral neck fracture was closely related to the degeneration of ComT and TenT. Trochanteric hip fractures were associated with a more severe degeneration in TroT as well as an enlargement of WT region besides the ComT and TenT degeneration. We concluded that the hip fragility fractures might be predicted by the measurement of the mean CT values in ComT, TenT, TroT and WT region. © 2013 Lu et al.; licensee BioMed Central Ltd.


PubMed | Capital Medical University, Pudong New Area District Zhoupu Hospital and China Japan Friendship Hospital
Type: Journal Article | Journal: Biomedical reports | Year: 2015

To investigate the effects of cellular membrane connexin 43 (Cx43) and the potential details in ischemic postconditioning (IPOC)-induced cardioprotection, ischemia/reperfusion (IR) models were generated in 8-week-old male Sprague-Dawley rats by ligating the left coronary artery anterior descending branch. The serum levels of myocardial creatases, nitric oxide (NO) and malondialdehyde (MDA) levels, infarct size, arrhythmia events, expression and distribution of Cx43, ultrastructure and apoptosis in the myocardium in different treatments with IR, IR + IPOC, IR + diazoxide or IR + IPOC + 5-hydroxydecanoate acid (5-HD) were investigated. Consequently, IPOC decreased infarct size (10.9 vs. 43.3%, P<0.01) and the levels of myocardial creatases, NO and MDA, and improved the expression (16.8 vs. 25.2% and 6.4 vs. 32.8%, after 1- and 3-h reperfusion, respectively; P<0.01) and distribution of Cx43, ultrastructure and apoptosis (19.2 vs. 42.9%, P<0.01) significantly. Diazoxide partly simulated the effects, and 5-HD attenuated but not completely abolished the effects of IPOC. In addition, the phosphorylated Cx43 (p-Cx43) level in the IR + IPOC group was lower than that in the IR + diazoxide group after 1-h reperfusion (26.1 vs. 29.4%, P>0.05); however, it was reversed after 3-h reperfusion and the p-Cx43 level in the IR + IPOC group was significantly higher than that in the IR + diazoxide group (32.8 vs. 18.7%, P<0.01). In conclusion, cell membrane Cx43 is also involved in the process of IPOC-induced cardioprotection and the improvement of membrane Cx43 is more dependent on mitochondrial K


PubMed | Fudan University and Pudong New Area District Zhoupu Hospital
Type: Journal Article | Journal: Oncology reports | Year: 2016

TRAIL is a tumor-selective apoptosis-inducing cytokine playing a vital role in the surveillance and elimination of some tumor cells. However, some tumors are resistant to TRAIL treatment. Proteasome inhibitor MG132 exhibits anti-proliferative and pro-apoptotic properties in many tumors. In this study, we demonstrated that proteasome inhibitor MG132 invitro and invivo potentiates TRAIL-induced apoptosis in gallbladder carcinoma GBC-SD cells. MG132 was able to inhibit the proliferation of GBC-SD cells and induce apoptosis in a dose-dependent manner. The induction of apoptosis by proteasome inhibitor MG132 was mainly through the extrinsic apoptotic pathways of caspase activation such as caspase-8, caspase-3 and PARP cleavage. In addition, this process was also dependent on the upregulation of death receptor 5 (DR5), which promoted TRAIL-induced apoptosis in GBC-SD cells. Taken together, these findings indicate that MG132 possesses anti-gallbladder cancer potential that correlate with regulation of DR5-dependent pathway, and suggest that MG132 may be a promising agent for sensitizing GBC-SD cells to TRAIL-induced apoptosis.


He H.,Capital Medical University | Zhao Z.-H.,Pudong New Area District Zhoupu Hospital | Han F.-S.,Capital Medical University | Wang X.-F.,Capital Medical University | Zeng Y.-J.,Capital Medical University
International Journal of Clinical and Experimental Medicine | Year: 2015

Objects: to probe into the effects of PKCε on migration and paracrine functions of stem cells and potential molecular mechanisms. Methods: Bone Marrow mesenchymal stem cells (BMMSCs) were obtained from rat femur and passaged. mRNA and protein levels of capital proteins in PKCε signaling, SDF-1/CXCR4 axis and PI3K/AKT pathway in the MSCs in different conditions treating with PKC agonist, specific PKCε inhibitor, CXCR4 antagonist or PI3K inhibitor for 24 hours were analyzed by real-time PCR and western blot, and migration abilities were observed by migration assay in vitro and the changes of paracrine factors in different treatments were analyzed by protein clips assay. Results: the levels of p-JNK, p-P38MAPK, SDF-1, CXCR4, PI3K and p-AKT increased significantly after treating with PKC agonist (P < 0.05) and decreased obviously after treating with specific PKCε inhibitor. Migration ability and paracrine function of MSCs were enhanced in PMA group and attenuated in PKCε inhibitor group, and inhibiting activity of CXCR4 or PI3K attenuated the effects of PKCε, but not abolished completely. Conclusion: There was cross-talking between PKCε signaling and SDF-1/CXCR4 axis and PI3K/AKT pathway in signal transduction of MSCs. Activating PKCε could improve migration ability and paracrine function of MSCs partly at least independent of SDF-1/CXCR4 axis and PI3K/AKT pathway. © 2015, E-Century Publishing Corporation. All Rights Reserved.


PubMed | Pudong New Area District Zhoupu Hospital
Type: | Journal: Drug design, development and therapy | Year: 2013

Modified chitosan nanoparticles are a promising platform for drug, such as 5-fluorouracil (5-FU), gene, and vaccine delivery. Here, we used chitosan and hepatoma cell-specific binding molecule glycyrrhetinic acid (GA) to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by infrared spectroscopy and hydrogen nuclear magnetic resonance. By combining GA-CTS and 5-FU, we obtained a GA-CTS/5-FU nanoparticle, with a particle size of 193.7 nm, drug loading of 1.56%, and a polydispersity index of 0.003. The GA-CTS/5-FU nanoparticle provided a sustained-release system comprising three distinct phases of quick, steady, and slow release. In vitro data indicated that it had a dose- and time-dependent anticancer effect. The effective drug exposure time against hepatic cancer cells was increased in comparison with that observed with 5-FU. In vivo studies on an orthotropic liver cancer mouse model demonstrated that GA-CTS/5-FU significantly inhibited cancer cell proliferation, resulting in increased survival time. The antitumor mechanisms for GA-CTS/5-FU nanoparticle were possibly associated with an increased expression of regulatory T-cells, decreased expression of cytotoxic T-cell and natural killer cells, and reduced levels of interleukin-2 and interferon gamma.


PubMed | Pudong New Area District Zhoupu Hospital
Type: Journal Article | Journal: Molecular cancer | Year: 2013

Cancer is both a systemic and a genetic disease. The pathogenesis of cancer might be related to dampened immunity. Host immunity recognizes nascent malignant cells - a process referred to as immune surveillance. Augmenting immune surveillance and suppressing immune escape are crucial in tumor immunotherapy.A recombinant plasmid capable of co-expressing granulocyte-macrophage colony- stimulating factor (GM-SCF), interleukin-21 (IL-21), and retinoic acid early transcription factor-1 (Rae-1) was constructed, and its effects determined in a mouse model of subcutaneous liver cancer. Serum specimens were assayed for IL-2 and INF- by ELISA. Liver cancer specimens were isolated for Rae-1 expression by RT-PCR and Western blot, and splenocytes were analyzed by flow cytometry.The recombinant plasmid inhibited the growth of liver cancer and prolonged survival of tumor-loaded mice. Activation of host immunity might have contributed to this effect by promoting increased numbers and cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL) following expression of GM-SCF, IL-21, and Rae-1. By contrast, the frequency of regulatory T cells was decreased, Consequently, activated CTL and NK cells enhanced their secretion of INF-, which promoted cytotoxicity of NK cells and CTL. Moreover, active CTL showed dramatic secretion of IL-2, which stimulates CTL. The recombinant expression plasmid also augmented Rae-1 expression by liver cancer cells. Rae-1 receptor expressing CTL and NK cells removed liver cancer.The recombinant expression plasmid inhibited liver cancer by a mechanism that involved activation of cell-mediated immunity and Rae-1 in liver cancer.


PubMed | Capital Medical University and PuDong New Area District ZhouPu Hospital
Type: | Journal: Cell death & disease | Year: 2016

We assessed the effects of protein kinase C (PKC) for improving stem cell therapy for acute myocardial infarction (AMI). Primary mesenchymal stem cells (MSCs) were harvested from rat bone marrow. PKC-overexpressed MSCs and control MSCs were transplanted into infarct border zones in a rat AMI model. MSCs and PKC distribution and expression of principal proteins involved in PKC signaling through the stromal cell-derived factor 1 (SDF-1)/CXC chemokine receptor type 4 (CXCR4) axis and the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway were analyzed by immunofluorescence and western blot 1 day after transplantation. Echocardiographic measurements and histologic studies were performed at 4 weeks after transplantation, and MSC survival, expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor (TGF), cardiac troponin I (cTnI), von Willebrand factor (vWF), smooth muscle actin (SMA) and factor VIII and apoptosis in infarct border zones were assessed. Rat heart muscles retained more MSCs and SDF-1, CXCR4, PI3K and phosphorylated AKT increased with PKC overexpression 1 day after transplantation. MSC survival and VEGF, bFGF, TGF, cTnI, vWF, SMA and factor VIII expression increased in animals with PKC-overexpressed MSCs at 4 weeks after transplantation and cardiac dysfunction and remodeling improved. Infarct size and apoptosis decreased as well. Inhibitory actions of CXCR4 or PI3K partly attenuated the effects of PKC. Activation of PKC may improve retention, survival and differentiation of transplanted MSCs in myocardia. Augmentation of PKC expression may enhance the therapeutic effects of stem cell therapy for AMI.

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