Chinese Institute of Clinical Medical Sciences

Beijing, China

Chinese Institute of Clinical Medical Sciences

Beijing, China
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Deng T.,Chinese Institute of Clinical Medical Sciences | Chen Q.,Peking Union Medical College | Han D.,Peking Union Medical College
Frontiers in Bioscience - Landmark | Year: 2016

Three members of a receptor tyrosine kinase family, including Tyro3, Axl, and Mer, are collectively called as TAM receptors. TAM receptors have two common ligands, namely, growth arrest specific gene 6 (Gas6) and protein S (ProS). The TAM-Gas6/ProS system is essential for phagocytic removal of apoptotic cells, and plays critical roles in regulating immune response. Genetic studies have shown that TAM receptors are essential regulators of the tissue homeostasis in immunoprivileged sites, including the testis, retina and brain. The mechanisms by which the TAM-Gas6/ProS system regulates the tissue homeostasis in immunoprivileged sites are emerging. The roles of the TAM-Gas6/ProS system in regulating the immune privilege were intensively investigated in the mouse testis, and several studies were performed in the eye and brain. This review summarizes our current understanding of TAM signaling in the testis and other immunoprivileged tissues, as well as highlights topics that are worthy of further investigation. © 1996-2016.

Shao K.,Fudan University | Huang R.,Fudan University | Li J.,Fudan University | Han L.,Fudan University | And 3 more authors.
Journal of Controlled Release | Year: 2010

Amphotericin B (AmB) is a poorly water soluble antibiotic and is used to treat fungal infections of the central nervous system (CNS). However, AmB shows poor penetration into the CNS. Angiopep-2, the ligand of low-density lipoprotein receptor-related protein (LRP) present on the BBB, exhibits higher transcytosis capacity and parenchymal accumulation, which allowed us to consider the selectivity of it for receptor-mediated drug targeting to the brain. With this in mind, we prepared angiopep-2 modified PE-PEG based micellar drug delivery system loaded with the antifungal drug AmB to evaluate the efficiency of AmB accumulating into the brain. PE-PEG based micelles as nano-scaled drug carriers were investigated by incorporating AmB with high drug entrapping efficiency, improving solubilization of AmB and reducing its toxicity to mammalian cells. The AmB-incorporated angiopep-2 modified micelles showed highest efficiency in penetrating across the blood-brain barrier (BBB) than unmodified micelles and Fungizone (deoxycholate amphotericin B) in vitro and in vivo. Meanwhile, contrary to the free Rho 123, the enhancement of Rho 123-incorporated angiopep-2 modified micelles across the BBB can be explained by angiopep-2 modified polymeric micelles that have a potential to overcome the activity of efflux proteins expressed on the BBB such as P-glycoprotein. In conclusion, angiopep-2 modified polymeric micelles could be developed as a novel drug delivery system for brain targeting. © 2010 Elsevier B.V.

He H.,CAS Beijing National Laboratory for Molecular | Li Y.,CAS Beijing National Laboratory for Molecular | Jia X.-R.,CAS Beijing National Laboratory for Molecular | Du J.,Peking University | And 4 more authors.
Biomaterials | Year: 2011

A dual-targeting drug carrier (PAMAM-PEG-WGA-Tf) based on the PEGylated fourth generation (G = 4.0) PAMAM dendrimer with transferrin (Tf) and wheat germ agglutinin (WGA) on the periphery and doxorubicin (DOX) loaded in the interior was synthesized and its BBB penetration and tumor targeting properties were explored. DLS and TEM measurements revealed the size of PAMAM-PEG-WGA-Tf was in the range of 14-20 nm. It reduced the cytotoxicity of DOX to the normal cells greatly, while efficiently inhibited the growth rate of the C6 glioma cells. The assay of transport across the BBB showed that PAMAM-PEG-WGA-Tf delivered 13.5% of DOX in a period of 2 h, demonstrating an enhanced transport ratio as compared to the ratio of 8% for PAMAM-PEG-WGA, 7% for PAMAM-PEG-Tf and 5% for free DOX in the same period of time. The accumulation of DOX in the tumor site was increased due to the targeting effects of both Tf and WGA, leading to the complete breakage of the avascular C6 glioma spheroids in vitro. © 2010 Elsevier Ltd.

Li Y.,CAS Beijing National Laboratory for Molecular | He H.,CAS Beijing National Laboratory for Molecular | Jia X.,CAS Beijing National Laboratory for Molecular | Lu W.-L.,Peking University | And 2 more authors.
Biomaterials | Year: 2012

A pH-sensitive dual-targeting drug carrier (G4-DOX-PEG-Tf-TAM) was synthesized with transferrin (Tf) conjugated on the exterior and Tamoxifen (TAM) in the interior of the fourth generation PAMAM dendrimers for enhancing the blood-brain barrier (BBB) transportation and improving the drug accumulation in the glioma cells. It was found that, on average, 7 doxorubicine (DOX) molecules, over 30 PEG 1000 and PEG 2000 chains and one Tf group were bonded on the periphery of each G4 PAMAM dendrimer, while 29 TAM molecules were encapsulated into the interior of per dendrimer. The pH-triggered DOX release was 32% at pH 4.5 and 6% at pH 7.4, indicating a comparatively fast drug release at weak acidic condition and stable state of the carrier at physiological environment. The in vitro assay of the drug transport across the BBB model showed that G4-DOX-PEG-Tf-TAM exhibited higher BBB transportation ability with the transporting ratio of 6.06% in 3 h. The carrier was internalized into C6 glioma cells upon crossing the BBB model by the coactions of TfR-mediated endocytosis and the inhibition effect of TAM to the drug efflux transports. Moreover, it also displayed the in vitro accumulation of DOX in the avascular C6 glioma spheroids made the tumor volume effectively reduced. © 2012 Elsevier Ltd.

Chiang Y.-C.,China Medical University at Taichung | Hung T.-W.,National Health Research Institute | Ho I.-K.,China Medical University at Taichung | Ho I.-K.,National Health Research Institute | Ho I.-K.,Chinese Institute of Clinical Medical Sciences
Addiction Biology | Year: 2014

Heroin use among young women of reproductive age has drawn much attention around the world. However, there is lack of information on the long-term effects of prenatal exposure to opioids on their offspring. Our previous study demonstrated that prenatally buprenorphine-exposed offspring showed a marked change in the cross-tolerance to morphine compared with other groups. In the current study, this animal model was used to study effects of methamphetamine (METH)-induced behavioral sensitization in the offspring at their adulthood. The results showed no differences in either basal or acute METH-induced locomotor activity in any of the groups of animals tested. When male offspring received METH injections of 2 mg/kg, i.p., once a day for 5 days, behavioral sensitization was induced, as determined by motor activity. Furthermore, the distance and rate of development (slope) of locomotor activity and conditioned place preference induced by METH were significantly increased in the prenatally buprenorphine-exposed animals compared with those in other groups. The dopamine D1R in the nucleus accumbens of the prenatally buprenorphine-exposed offspring had lower mRNA expression; but no significant changes in the μ-, κ-opioid, nociceptin, D2R and D3R receptors were noted. Furthermore, significant alterations were observed in the basal level of cAMP and the D1R agonist enhanced adenylyl cyclase activity in the prenatally buprenorphine-exposed group. Overall, the study demonstrates that D1R and its downregulated cAMP signals are involved in enhancing METH-induced behavioral sensitization in prenatally buprenorphine-exposed offspring. The study reveals that prenatal exposure to buprenorphine caused long-term effects on offspring and affected the dopaminergic system-related reward mechanism. © 2013 Society for the Study of Addiction.

Yang H.-Y.,Chinese Institute of Clinical Medical Sciences | Wu X.-M.,Chinese Institute of Clinical Medical Sciences | Liu Y.,Jiangxi Province Peoples Hospital | He D.,Chinese Institute of Clinical Medical Sciences
Transplantation | Year: 2015

Background Chronic ethanol exposure leads to permanent damage to the central nervous system and produces cognitive deficits such as learning and memory impairment. The present study was designed to explore the therapeutic effect of bone marrow mesenchymal stem cells (BMMSCs) on a rat model of alcohol-associated dementia (AAD). Methods Bone marrow mesenchymal stem cells were prelabeled with 4',6-diamidino-2-phenylindole and directly transplanted into the hippocampus of AAD rats, an important site of alcohol effects that lead to cognitive deficits. The therapeutic effect of BMMSCs was evaluated by observing Morris water maze behavior, hippocampus morphology, and neuronal apoptosis. Still, the activities of antioxidant enzymes including total superoxide dismutase and glutathione peroxidase in rat hippocampus were measured, and the expression of brain-derived neurotrophic factor in rat hippocampus was also detected by the method of immunohistochemistry. Results Transplantation of BMMSCs directly into the hippocampus significantly improved the learning and memory function of AAD rats and prevented alcohol-induced hippocampal damages. Moreover, BMMSC transplantation inhibited neuron cell apoptosis and increased the activity of total superoxide dismutase in the hippocampus. Moreover, transplantation of BMMSCs improved the protein level of brain-derived neurotrophic factor in the hippocampus in parallel with behavioral and histologic recovery for AAD rats. Conclusions The findings indicate that the functional benefit observed in the BMMSC-grafted AAD rats is caused by the reduction of oxidative damage and the production of trophic factors by BMMSCs. Bone marrow mesenchymal stem-cell transplantation may be a useful and feasible method for clinical treatment of alcohol-induced brain injuries. © 2015 Wolters Kluwer Health, Inc.

Liu Y.,Fudan University | Li J.,Fudan University | Shao K.,Fudan University | Huang R.,Fudan University | And 3 more authors.
Biomaterials | Year: 2010

The blood-brain barrier is the major obstacle that prevents diagnostic and therapeutic drugs being delivered to the central nervous systems in order to exert their effects. Specific ligand-receptor binding mediated endocytosis is one of the possible strategies to cross this barrier. A 30-amino-acid peptide (leptin30) derived from an endogenic hormone-leptin is exploited as brain-targeting ligand as it is reported to possess the same brain accumulation efficiency after intravenous injection. Dendrigraft poly-l-lysine (DGL) is used as non-viral gene vector in this study. DGL-PEG-Leptin30 was complexed with plasmid DNA yielding nanoparticles (NPs). The cellular uptake characteristic and mechanism were explored in brain capillary endothelial cells (BCECs) which express leptin receptors. Furthermore, brain parenchyma microglia cells such as BV-2 cells expressing leptin receptors could promote ligand-receptor mediated endocytosis leading to enhanced gene transfection ability of DGL-PEG-Leptin30/DNA NPs. The targeted NPs were proved to be transported across in vitro BBB model effectively and accumulate more in brains after i.v. resulting in a relatively high gene transfection efficiency both in vitro and in vivo. Besides, the NPs showed low cytotoxicity after in vitro transfection. Thus, DGL-PEG-Leptin30 provides a safe and noninvasive approach for the delivery of gene across the blood-brain barrier. © 2010 Elsevier Ltd.

Xia Q.S.,Chinese Institute of Clinical Medical Sciences
Zhonghua yi xue za zhi | Year: 2010

OBJECTIVE: To investigate the effect of anti-cancer drugs on the expression of B-cell integration cluster (BIC) RNA/miRNA-155 in human pancreatic cancer PANC-1 cells. METHODS: PANC-1 cells were treated with different concentrations of anti-cancer drugs. Total RNA of the treated cells were harvested and the expression levels of BIC RNA and mature miR-155 were quantified by using Taqman FAM/MGB probes on a real-time PCR system. Relative quantification was carried out using the DeltaDeltaCt method. A PI3K-related kinases inhibitor was used to determine whether these kinases were involved in the regulation of BIC RNA. RESULTS: The expression of BIC RNA was strongly induced by anti-cancer drugs. When PANC-1 cells were treated by gemcitabine with concentrations of 1.0, 2.5, 5.0, 10.0 mg/L for 48 h and 72 h, the level of BIC RNA (48 h: 37.1 +/- 4.1, 29.0 +/- 5.7, 21.0 +/- 7.6, 40.4 +/- 9.0, 72 h: 27.7 +/- 3.1, 43.1 +/- 1.2, 31.8 +/- 5.4, 23.1 +/- 1.4) were significantly higher than that of the control (48 h: 1.6 +/- 1.1, 72 h: 1.0 +/- 0.1, all P < 0.05). 5-FU (10 mg/L, 48 h) and bleomycin (100 mg/L, 48 h) also induced BIC RNA up-regulation (5.2 +/- 1.1 vs 1.7 +/- 0.7, 11.5 +/- 0.7 vs 1.7 +/- 0.7, both P < 0.05). When PANC-1 cells treated with 1.0, 2.5, 5.0, 10.0 mg/L gemcitabine for 72 h, the level of miR-155 (2.21 +/- 0.40, 1.86 +/- 0.03, 2.47 +/- 0.04, 3.24 +/- 0.05) also higher than that of the control (1.11 +/- 0.09, P < 0.05), while no change was observed when the cells only treated for 48 h. Further study showed gemcitabine-induced BIC RNA up-regulation was inhibited by wortmannin, a specific PI3K inhibitor, the expression levels of BIC RNA of 1 micromol/L wortmannin + 5 mg/L gemcitabine group and 10 micromol/L wortmannin + 5 mg/L gemcitabine group were 5.34 +/- 1.11 and 1.26 +/- 0.07, lower than that of 5 mg/L gemcitabine group (11.82 +/- 3.11, P < 0.05). CONCLUSIONS: BIC RNA is strongly induced by anti-cancer drugs in PANC-1 cells and the levels of miR-155 also slightly increase. PI3K pathway is involved in gemcitabine-induced BIC RNA up-regulation.

D'Ascenzo F.,Chinese Institute of Clinical Medical Sciences
Journal of Cardiovascular Medicine | Year: 2016

BACKGROUND: Bleeding events after an acute coronary syndrome have a negative impact on prognosis. Available risk scores are limited by suboptimal accuracy, prediction of only in-hospital events and absence of patients treated with new antiplatelet agents in the current era of widespread use of percutaneous coronary intervention. DESIGN: The BleeMACS (Bleeding complications in a Multicenter registry of patients discharged after an Acute Coronary Syndrome) project is a multicenter investigator-initiated international retrospective registry that enrolled more than 15?000 patients discharged with a definitive diagnosis of acute coronary syndrome and treated with percutaneous revascularization. The primary end point is the incidence of major bleeding events requiring hospitalization and/or red cell transfusion concentrates within 1 year. An integer risk score for bleeding within the first year after hospital discharge will be developed from a multivariate competing-risks regression. CONCLUSION: The BleeMACS registry collaborative will allow development and validation of a risk score for prediction of major bleeding during follow-up for patients receiving contemporary therapies for acute coronary syndrome. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Zhong S.L.,Chinese Institute of Clinical Medical Sciences
Pharmacogenetics and genomics | Year: 2012

Compared with genetic factors, drug interactions are largely unexplored in pharmacogenetic studies. This study sought to systematically investigate the effects of VKORC1, STX4A, CYP2C9, CYP4F2, CYP3A4, and GGCX gene polymorphisms and interacting drugs on warfarin maintenance dose. A retrospective study of 845 Chinese patients after heart valve replacement receiving long-term warfarin maintenance therapy was conducted. Thirteen polymorphisms in the six genes were genotyped, and 36 drugs that may interact with warfarin were investigated. Single-nucleotide polymorphism association analysis showed that VKORC1, CYP2C9 and CYP4F2 variations were highly associated with the warfarin maintenance dose. Among 36 drugs that may interact with warfarin, fluconazole, amiodarone, and omeprazole were associated with the requirement for 45.8, 16.7, and 16.7% lower median warfarin dose (all P<0.05 with a false discovery rate <0.05). The final pharmacogenetic equation explained 43.65% of interindividual variation of warfarin maintenance dose with age, body surface area, VKORC1 g.3588G>A, CYP2C9*3, CYP4F2 c.1297G>A, amiodarone, fluconazole, and diltiazem accounting for 1.97, 2.74, 24.12, 3.94, 1.64, 5.92, 2.47, and 0.84% of variation. The present study indicated that VKORC1, CYP4F2, and CYP2C9 genotypes and interacting drugs had a significant impact on the warfarin maintenance dose in Chinese patients with heart valve replacement and demonstrated that integrating interacting drugs can largely improve the predictability of the dose algorithm.

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