Wei Kong

Peking University Health Science Center, Peping, Beijing, China

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Publications (179)605.91 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Acute aortic dissection (AAD) is a life-threatening cardiovascular disease caused by progressive medial degeneration of the aortic wall. A disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) is a recently identified extracellular metalloproteinase participating in the development of vascular disease, such as atherosclerosis. In the present study, we found that ADAMTS1 was significantly elevated in blood samples from AAD patients compared with patients with acute myocardial infarction and healthy volunteers. Based on these findings, we established an AAD model by infusing angiotensin II in older mice. AAD was successfully developed in aorta tissues, with an incidence of 42% after 14 days in the angiotensin II group. Macrophage and neutrophil infiltration was observed in the media of the aorta, and ADAMTS1 overexpression was found in the aorta by Western blot and immunohistochemistry. Double immunofluorescence staining showed the expression of ADAMTS1 in macrophages and neutrophils. Consistent with the upregulation of ADAMTS1 in aortic dissection tissues, versican (a proteoglycan substrate of ADAMTS1) was degraded significantly more in these tissues than in control aortic tissues. These data suggest that the increased expression of ADAMTS1 protein in macrophages and neutrophils that infiltrated aortic tissues may promote the progression of AAD by degrading versican.
    Science China. Life sciences 11/2015; DOI:10.1007/s11427-015-4959-4 · 1.69 Impact Factor
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    ABSTRACT: Objective: Chronic administration of selective cyclooxygenase-2 (COX-2) inhibitors leads to an increased risk of adverse cardiovascular events, including myocardial infarction and stroke. Vascular smooth muscle cell (VSMC) calcification, a common complication of chronic kidney disease, is directly related to cardiovascular morbidity and mortality. Here, we tested whether specific COX-2 inhibition affects vascular calcification during chronic renal failure. Approach and results: The COX-2-specific inhibitors NS398 and SC236 significantly increased high-phosphate (Pi)-induced VSMC calcification. Similarly, COX-2(-/-) VSMCs, COX-2(-/-) aortas rings treated with high Pi and adenine diet-induced COX-2(-/-) chronic renal failure mice displayed enhanced calcium deposition. Metabolomic analysis revealed the differential suppression of PGE2 production by COX-1- and COX-2-specific inhibitors in high-Pi-stimulated VSMCs, indicating the involvement of PGE2 during COX-2 inhibition-aggravated vascular calcification. Indeed, exogenous PGE2 reduced alkaline phosphatase activity, osteogenic transdifferentiation, apoptosis, and calcification of VSMCs. In accordance, downregulation of microsomal prostaglandin E synthase (mPGES)-1 in VSMCs, mPGES-1(-/-) aorta with high-Pi stimulation and mPGES-1(-/-) chronic renal failure mice resulted in enhanced vascular mineralization. Further applications of RNAi and specific antagonists for PGE2 receptors indicated EP4 may mediate PGE2-inhibited vascular calcification. Conclusions: Our data revealed the pivotal role of COX-2-mPGES-1-PGE2 axis in vascular calcification. The selective inhibition of COX-2 or mPGES-1 may increase the risk of calcification and subsequent adverse cardiovascular events during chronic renal failure.
    Arteriosclerosis Thrombosis and Vascular Biology 11/2015; DOI:10.1161/ATVBAHA.115.306642 · 6.00 Impact Factor
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    ABSTRACT: Enterovirus 71 (EV71) and Coxsackievirus A16 (CVA16), as the main agents causing hand, foot and mouth disease (HFMD), have become a serious public health concern in the Asia-Pacific region. Recently, various neutralizing B cell epitopes of EV71 were identified as targets for promising vaccine candidates. Structural studies of Picornaviridae indicated that potent immunodominant epitopes typically lie in the hypervariable loop of capsid surfaces. However, cross-neutralizing antibodies and cross-protection between EV71 and CVA16 have not been observed. Therefore, we speculated that divergent sequences of the two viruses are key epitopes for inducing protective neutralizing responses. In this study, we selected 10 divergent epitope candidates based on alignment of the EV71 and CVA16 P1 amino acid sequences using the Multalin interface page, and these epitopes are conserved among all subgenotypes of EV71. Simultaneously, by utilizing the norovirus P particle as a novel vaccine delivery carrier, we identified the 71-6 epitope (amino acid 176-190 of VP3) as a conformational neutralizing epitope against EV71 in an in vitro micro-neutralization assay as well as an in vivo protection assay in mice. Altogether, these results indicated that the incorporation of the 71-6 epitope into the norovirus P domain can provide a promising candidate for an effective synthetic peptide-based vaccine against EV71.
    Vaccine 11/2015; DOI:10.1016/j.vaccine.2015.10.104 · 3.62 Impact Factor
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    Kexin Zhang · Tuoyi Li · Yi Fu · Qinghua Cui · Wei Kong ·
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    ABSTRACT: Abdominal aortic aneurysm (AAA) is frequently lethal and has no effective pharmaceutical treatment, posing a great threat to human health. Previous bioinformatics studies of the mechanisms underlying AAA relied largely on the detection of direct protein-protein interactions (level-1 PPI) between the products of reported AAA-related genes. Thus, some proteins not suspected to be directly linked to previously reported genes of pivotal importance to AAA might have been missed. In this study, we constructed an indirect protein-protein interaction (level-2 PPI) network based on common interacting proteins encoded by known AAA-related genes and successfully predicted previously unreported AAA-related genes using this network. We used four methods to test and verify the performance of this level-2 PPI network: cross validation, human AAA mRNA chip array comparison, literature mining, and verification in a mouse CaPO4 AAA model. We confirmed that the new level-2 PPI network is superior to the original level-1 PPI network and proved that the top 100 candidate genes predicted by the level-2 PPI network shared similar GO functions and KEGG pathways compared with positive genes.
    PLoS ONE 10/2015; 10(10):e0140888. DOI:10.1371/journal.pone.0140888 · 3.23 Impact Factor
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    ABSTRACT: Lethal rabies can be prevented effectively by post-exposure prophylactic (PEP) with rabies immunoglobulin (RIG). Single-chain variable fragment (scFv), which is composed of a variable heavy chain (VH) and variable light chain (VL) connected by a peptide linker, may be developed as alternative to RIG for neutralizing rabies virus (RV). However, our previously constructed scFv (FV57S) with the (NH2) VH-linker-VL (COOH) orientation showed a lower neutralizing potency than its parent RIG. This orientation may inhibit FV57S from refolding into an intact and correct conformation. Therefore, the RFV57S protein with a VL-linker-VH orientation was constructed based on FV57S. A HIS tag was incorporated to aid in purification and detection of RFV57S and FV57S. However, abilities of RFV57S and FV57S to bind with the anti-HIS tag mAb were different. Therefore, a novel direct ELISA was established by utilizing a biotin-labeled truncated glycoprotein of RV. Although with similar stability and in vitro neutralizing potency as FV57S, RFV57S showed enhanced binding ability, affinity and in vivo protective efficacy against lethal dose of RV. Our studies support the feasibility of developing a scFv with reversed orientation and provide a novel method for evaluating the binding ability, stability and affinity of engineered antibodies recognizing linear epitope.
    Protein and Peptide Letters 10/2015; · 1.07 Impact Factor

  • PLoS ONE 10/2015; 10(10):e0140515. DOI:10.1371/journal.pone.0140515 · 3.23 Impact Factor
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    ABSTRACT: Eliciting efficient broadly neutralizing antibodies (BnAbs) is a major goal in vaccine development against human immunodeficiency virus type 1 (HIV-1). Conserved epitopes in the membrane-proximal external region (MPER) of HIV-1 are a significant target. In this study, Norovirus P particles (NoV PPs) were used as carriers to display conformational 4E10 and 10E8 epitopes in different patterns with an appropriate linker. Immune responses to the recombinant NoV PPs were characterized in guinea pigs and Balb/c mice and could induce high levels of MPER-binding antibodies. Modest neutralizing activities could be detected in sera of guinea pigs but not of Balb/c mice. The 4E10 or 10E8 epitopes dispersed on three loops on the outermost surface of NoV PPs (4E10-loop123 PP or 10E8-loop123 PP) elicited higher neutralizing activities than the equivalent number of epitopes presented on loop 2 only (4E10-3loop2 PP or 10E8-3loop2 PP). The epitopes on different loops of PP were well-exposed and likely formed an appropriate conformation to induce neutralizing antibodies. Although sera of immunized guinea pigs could neutralize several HIV envelope-pseudoviruses, a vaccine candidate for efficiently inducing HIV-1 BnAbs remains to be developed.
    Immunology letters 10/2015; DOI:10.1016/j.imlet.2015.10.003 · 2.51 Impact Factor
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    ABSTRACT: Here, we describe a process for expression, purification, and characterization of truncated human papillomavirus type-6 (HPV-6) L1 virus-like particles (VLPs). The scalable cultivation process in a WAVE Bioreactor at the 10-L scale was optimized to express HPV-6 L1 VLPs using the baculovirus insect expression system. A hollow fiber membrane system was used for the integrated operation, including concentration, diafiltration, extraction, and clarification. The HPV-6 L1 protein was further purified by anion-exchange chromatography and hydrophobic chromatography. The HPV-6 L1 protein could self-assemble into VLPs with a diameter of approximately 50-60 nm after removal of the reductant dithiothreitol (DTT). The final purified HPV-6 L1 VLPs product was characterized to estimate yield and purity, and exceeds the requirements for pharmaceutical-grade VLP vaccine. Immunization of mice demonstrated that the vaccine could elicit high titer neutralizing antibodies in vivo. This study confirms the feasibility of producing pharmaceutical-grade HPV type-6 L1 VLPs on an industrial scale for clinical trials.
    Applied Microbiology and Biotechnology 10/2015; DOI:10.1007/s00253-015-6974-6 · 3.34 Impact Factor
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    ABSTRACT: BST2 (CD317, tetherin, HM1.24) is an interferon-inducible transmembrane protein which can directly inhibit the release of enveloped virus particles from infected cells, and its anti-viral activity is reported to be related to the specific topological arrangement of its four structural domains. The N-terminal cytoplasmic tail of feline BST2 (fBST2) is characterized by a shorter N-terminal region compared to those of other known homologs. In this study, we investigated the functional impact of modifying the cytoplasmic tail region of fBST2 and its molecular mechanism. The fBST2 protein with the addition of a peptide at the N-terminus retained anti-release activity against human immunodeficiency virus type-1 and pseudovirus based on feline immunodeficiency virus at a weaker level compared with the wild-type fBST2. However, the fBST2 protein with addition of a peptide internally in the ectodomain proximal to the GPI anchor still retained its anti-viral activity well. Notably, the N-glycosylation state and the cell surface level of the N-terminally modified variants were unlike those of the wild-type protein, while no difference was observed in their intracellular localizations. However, in contrast to human BST2, the wild-type fBST2 did not show the ability to activate NF-κB. Consistent with previous reports, our findings showed that adding a peptide in the cytoplasmic tail region of fBST2 may influence its anti-viral activity. The shorter N-terminal cytoplasmic region of fBST2 compared with human BST2 did not apparently affect its anti-viral activity, which is independent of its N-glycosylation and ability to activate NF-κB.
    PLoS ONE 09/2015; 10(9):e0138190. DOI:10.1371/journal.pone.0138190 · 3.23 Impact Factor
  • Lu Fu · Yingnan Li · Yue Hu · Bin Yu · Haihong Zhang · Jiaxin Wu · Hui Wu · Xianghui Yu · Wei Kong ·
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    ABSTRACT: Active vaccination against amyloid β (Aβ42) is considered a potential therapeutic approach for Alzheimer's disease (AD). However, immunization with synthetic human Aβ1-42 has resulted in meningoencephalitis in 6% of patients and generated only low-titer anti-Aβ42 antibodies. In order to develop a safe and effective vaccine against Alzheimer's disease, the Aβ1-6 peptide was used as the novel immunogen and Norovirus P particles as the vaccine platform in this study. By inserting and presenting Aβ1-6 on the outermost surface of the P particle, we showed that the chimeric P particle-based AD protein vaccine could elicit a strong immune response, inducing highly specific antibody titers against Aβ42 without causing T-cell activation. Furthermore, antibodies induced by the AD protein vaccines were demonstrated to be effective at the cellular level. In addition, we also compared the immunogenicity of the chimeric P particles with different insertional loci in the loop structure domain and demonstrated that insertion of the antigen into all three loops of the P particle at the same time could significantly improve immune responses to the vaccine. In conclusion, the Norovirus P particle is an excellent vaccine platform for stimulating Aβ42 antibody production, and chimeric P particles may be developed as an effective therapy for AD.
    Immunology letters 09/2015; 168(1). DOI:10.1016/j.imlet.2015.09.002 · 2.51 Impact Factor
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    ABSTRACT: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is capable of selectively inducing apoptosis of cancer cells, is a potential targeted drug for cancer therapy. The TRAIL protein induces apoptosis only in trimeric form. However, the recombinant soluble TRAIL (sTRAIL) trimer has low stability and a short half-life, which is a major obstacle for its advancement into clinical trials. Moreover, a percentage of engineered sTRAIL proteins are produced as dimers which may be toxic to normal human hepatocytes. In this study, we inserted three copies of the same subunit fragment of sTRAIL with a His tag into a polycistronic expression vector (pST39) to explore whether it would increase the proportion of trimers. We also constructed a heterozygous vector containing three subunit fragments of sTRAIL each with a different tag (His, HA, and Cmyc). Hybrid sTRAIL proteins (P-dTags) mainly as heterologous trimers were obtained by elution with a low concentration of imidazole based on different binding affinities of His with a nickel column. Functional analysis demonstrated that heterotrimeric forms of sTRAIL showed more stable activity compared to the P-3H at 4 °C but not at 37 °C without alteration in the native killing capacity. In addition, the heterologous trimers showed decreased toxicity to hepatocytes. These results suggest that the polycistronic expression system may be useful for expression of recombinant sTRAIL and improving its potential in cancer therapeutic applications. Copyright © 2015. Published by Elsevier Inc.
    Protein Expression and Purification 08/2015; 115. DOI:10.1016/j.pep.2015.08.004 · 1.70 Impact Factor
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    ABSTRACT: The study aims to develop a novel multistep chromatographic purification process for human enterovirus71 virus-like particles (VLPs) produced from insect cells (Sf9) infected with recombinant baculovirus. Sf9 cells were maintained in the Wave Bioreactor system20/50, and harvested when the viability decreased to 75% after infected with Bac-P1-3CD at the multiplicity of infection (MOI) of 1. After sonication and centrifugation, EV71 VLPs were purified with Capto(™) Core 700, Capto(™) adhere and Capto(TM) butyl. The purity was then determined by SDS-PAGE, Western blotting and high-performance liquid chromatography (HPLC), while the diameter of purified EV71 VLPs was analyzed by Dynamic Light Scattering (DLS) and Transmission electron microscopy (TEM). Immunization of BALB/c mice and serum collection were performed after contamination analysis, and neutralization antibodies were then analyzed by pseudovirus-based microneutralization assay. Results showed that these purified EV71 VLPs can be successfully purified with ~31.52% yield and > 95% purity. They could elicit stronger neutralization antibodies in mice compared with those produced from formalin-inactivated EV71 virus. Our results demonstrated that EV71 VLPs can be purified with the multistep chromatographic protocol. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Applied Microbiology 08/2015; 119(4). DOI:10.1111/jam.12922 · 2.48 Impact Factor
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    ABSTRACT: Fatal rabies can be prevented effectively by post-exposure prophylactic (PEP) with rabies immunoglobulin (RIG). Single-chain variable fragments (scFv), which are composed of a variable heavy chain (VH) and a variable light chain (VL) connected by a peptide linker, can potentially be used to replace RIG. However, in our previous study, a scFv (scFV57S) specific for the rabies virus (RV) G protein showed a lower neutralizing potency than that of its parent IgG due to lower stability and altered peptide assembly pattern. In monoclonal antibodies, the VH and VL interact non-covalently, while in scFvs the VH is connected covalently with the VL by the artificial linker. In this study, we constructed and expressed two peptides 57VL-JUN-HIS and 57VH-FOS-HA in Escherichia coli. The well-known Fos and Jun leucine zippers were utilized to dimerize VH and VL similarly to the IgG counterpart. The two peptides assembled to form zipFv57S in vitro. Due to the greater similarity in structure with IgG, the zipFv57S protein showed a higher binding ability and affinity resulting in notable improvement of in vitro neutralizing activity over its corresponding scFv. The zipFv57S protein was also found to be more stable and showed similar protective rate as RIG in mice challenged with a lethal dose of RV. Our results not only indicated zipFv57S as an ideal alternative for RIG in PEP but also offered a novel and efficient hetero-dimerization pattern of VH and VL leading to enhanced neutralizing potency. Copyright © 2015. Published by Elsevier Ltd.
    Molecular Immunology 08/2015; DOI:10.1016/j.molimm.2015.06.027 · 2.97 Impact Factor
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    ABSTRACT: Here is reported a novel pneumolysin(Ply) mutant(PlyM2) that addresses a long-standing problem for vaccine development in this field: detoxification of Ply in the premise of retaining antigenic integrity. Structure and function of wild-type Ply(PlyWT) and PlyM2 mutants were detected and compared. Their structures were not significantly different according to the analysis by thermal-dependent fluorescence spectroscopy and circular dichroism spectroscopy. PlyM2 was confirmed to have lost hemolytic activity and yet could induce neutralizing antibodies to prevent in vitro hemolysis by PlyWT and S. Pneumoniae. These results give support to PlyM2 to be a new protein antigen for inclusion in the development of an effective pneumococcal multiprotein vaccine.
    Chemical Research in Chinese Universities 08/2015; 31(4). DOI:10.1007/s40242-015-5105-3 · 0.88 Impact Factor
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    ABSTRACT: In this study, a novel glycol chitosan (GCS)-bestatin conjugate was synthesized and evaluated to demonstrate its efficacy in protecting thymopoietin oligopeptides from aminopeptidase-mediated degradation. Moreover, the mechanism and relative susceptibility of three thymopoietin oligopeptides, thymocartin (TP4), thymopentin (TP5), and thymotrinan (TP3), to enzymatic degradation were investigated and compared at the molecular level. Initial investigations indicated that formation of the GCS-bestatin conjugate, with a substitution degree of 7.0% (moles of bestatin per mole of glycol glucosamine unit), could significantly protect all three peptides from aminopeptidase-mediated degradation in a concentration-dependent manner. The space hindrance and loss of one pair of hydrogen bonds, resulting from the covalent conjugation of chitosan with bestatin, did not affect the specific interaction between bestatin and aminopeptidase. Moreover, TP4 displayed a higher degradation clearance compared with those of TP5 and TP3 under the same experimental conditions. The varying levels of susceptibility of these three peptides to aminopeptidase (TP4 > TP5 > TP3) were closely related to differences in their binding energies to enzyme, which mainly involved Van der Waals forces and electrostatic interactions, as supported by the results of molecular dynamics simulations. These results suggest that GCS-bestatin conjugate might be useful in the delivery of thymopoietin oligopeptides by mucosal routes, and that TP3 and TP5 are better alternatives to TP4 for delivery because of their robust resistance against enzymatic degradation. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.
    Journal of Pharmaceutical Sciences 07/2015; DOI:10.1002/jps.24567 · 2.59 Impact Factor
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    ABSTRACT: The absence of a productive cell culture system hampered detailed analysis of the structure and protein composition of the hepatitis E virion. In this study, hepatitis E virus from a robust HEV cell culture system and from the feces of infected monkeys at the peak of virus excretion was purified by ultra-centrifugation. The common feature of the two samples after ultracentrifugation was that the ORF2 protein mainly remained in the top fractions. The ORF2 protein from cell culture system was glycosylated, with an apparent molecular weight of 88 kDa, and was not infectious in PLC/PRF/5 cells. The ORF2 protein in this fraction can bind to and protect HEV RNA from digestion by RNase A. The RNA-ORF2 product has a similar sedimentation coefficient to the virus from feces. The viral RNA in the cell culture supernatant was mainly in the fraction of 1.15g/cm3 but that from the feces was mainly in the fraction of 1.21 g/cm3. Both were infectious in PLC/PRF/5 cells. And the fraction in the middle of the gradient (1.06g/cm3) from the cell culture supernatant,but not that from the feces, also has ORF2 protein and HEV RNA but was not infectious in PLC/PRF/5.The infectious RNA-rich fraction from the cell culture contained ORF3 protein and lipid but the corresponding fraction from feces had no lipid and little ORF3 protein. The lipid on the surface of the virus has no effect on its binding to cells but the ORF3 protein interferes with binding. The result suggests that most of the secreted ORF2 protein is not associated with HEV RNA and that hepatitis E virus produced in cell culture differs in structure from the virus found in feces in that it has a lipid envelope.
    PLoS ONE 07/2015; 10(7):e0132503. DOI:10.1371/journal.pone.0132503 · 3.23 Impact Factor
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    ABSTRACT: Plant proteins have been drawing increasing attention owing to their safety, abundance and relatively low cost in comparison with animal proteins. The development of plant protein-based delivery vehicles may lead to the provision of novel pharmaceutical products to patients. Zein is a class of alcohol-soluble prolamine proteins present in maize endosperm that was approved as a generally recognised as safe excipient in 1985 by the US FDA for use in pharmaceutical film coatings. Over the past few decades, numerous studies have been carried out to illustrate zein’s potential for novel applications in the biomedical field. This paper reviews the present status of zein-based nanofibres, with emphasis on their fabrication and biomedical applications, particularly for drug delivery. Their benefits and limitations are also discussed to provide further insight into zein’s potential as a promising biomaterial.
    Current Pharmaceutical Design 07/2015; 21(22). DOI:10.2174/1381612821666150531170448 · 3.45 Impact Factor
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    ABSTRACT: Despite significant efforts directed toward research on HIV-1 vaccines, a truly effective immunogen has not been achieved. However, the broadly neutralizing antibodies (BnAbs) 2F5 and 4E10, targeting the highly conserved membrane proximal external region (MPER) of HIV-1, are two promising tools for vaccine development. Here we engrafted the MPER into the linker domain between the trimeric core structure and the transmembrane domain of influenza A virus HA2 to investigate the potential of such chimeric viruses to elicit HIV-1 neutralizing antibodies. In the context of proliferating attenuated influenza A viruses, these HIV-1 neutralizing antibody epitopes could be continuously expressed and mimicked their native conformation to induce humoral immune responses. While MPER-specific antibodies could be detected in serum of guinea pigs vaccinated with the chimeric viruses, they exhibited only weakly neutralizing activities. These antisera from vaccinated animals neutralized viruses of clades B and BC (tier 1), but not of clades AE (tier 1) and C (tier 2). These results suggest that influenza A virus can be used as a vehicle for displaying MPER and inducing BnAbs, but it provides limited protection against HIV-1 infection. In the future development of HIV-1 vaccines by rational design, a more effective live virus vector or multiple antigens should be chosen to facilitate the process of neutralizing antibody maturation. Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 06/2015; 33(32). DOI:10.1016/j.vaccine.2015.06.072 · 3.62 Impact Factor
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    ABSTRACT: Streptococcus pneumoniae is an important pathogen accounting for a large number of deaths worldwide. Due to drawbacks of the current polysaccharide-based vaccine, the most promising way to generate an improved vaccine may be to utilize protection-eliciting pneumococcal proteins. Pneumococcal surface adhesin A (PsaA) and pneumococcal surface protein A (PspA) are two vaccine candidates which have been evaluated against S. pneumoniae infection in animal models or human clinical trials with encouraging results. In this study, the efficacy of the fusion protein PsaA-PspA, which includes PsaA part and PspA part, in inducing immunoprotective effects against fatal pneumococcal challenge was evaluated in an animal model. PspA part of PsaA-PspA fusion protein contains both family1 N-terminal region and family 2 N-terminal clade-defining region of PspA. Immunization with the PsaA-PspA fusion protein induced high levels of antibodies against both PsaA and PspA, which could bind to intact S. pneumoniae strains bearing different PspAs. Ex vivo stimulation of splenocytes from mice immunized with PsaA-PspA induced IL-17A secretion. Mice immunized with PsaA-PspA showed reduced S. pneumoniae levels in the blood and lungs compared with the PBS group after intranasal infection. Finally, mice immunized with PsaA-PspA fusion proteins were protected against fatal challenge with pneumococcal strains expressing different PspAs regardless of the challenge route. These results support the PsaA-PspA fusion protein as a promising vaccine strategy, as demonstrated by its ability to enhance the immune response and stimulate production of high titer antibodies against S. pneumoniae strains bearing heterologous PspAs, as well as confer protection against fatal challenge with PspA family 1 and family 2 strains.
    Immunological Investigations 06/2015; 44(5):482-96. DOI:10.3109/08820139.2015.1037956 · 1.99 Impact Factor
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    ABSTRACT: Vascular calcification (VC) is a major risk factor for cardiovascular mortality in chronic renal failure (CRF) patients, but the pathogenesis remains partially unknown and effective therapeutic targets should be urgently explored. Here we pursued the therapeutic role of rapamycin in CRF-related VC. Mammalian target of rapamycin (mTOR) signal was activated in the aortic wall of CRF rats. As expected, oral rapamycin administration significantly reduced VC by inhibiting mTOR in rats with CRF. Further in vitro results showed that activation of mTOR by both pharmacological agent and genetic method promoted, while inhibition of mTOR reduced, inorganic phosphate-induced vascular smooth muscle cell (VSMC) calcification and chondrogenic/osteogenic gene expression, which were independent of autophagy and apoptosis. Interestingly, the expression of Klotho, an antiaging gene that suppresses VC, was reduced in calcified vasculature, whereas rapamycin reversed membrane and secreted Klotho decline through mTOR inhibition. When mTOR signaling was enhanced by either mTOR overexpression or deletion of tuberous sclerosis 1, Klotho mRNA was further decreased in phosphate-treated VSMCs, suggesting a vital association between mTOR signaling and Klotho expression. More importantly, rapamycin failed to reduce VC in the absence of Klotho by using either siRNA knockdown of Klotho or Klotho knockout mice. Thus, Klotho has a critical role in mediating the observed decrease in calcification by rapamycin in vitro and in vivo.Kidney International advance online publication, 10 June 2015; doi:10.1038/ki.2015.160.
    Kidney International 06/2015; 88(4). DOI:10.1038/ki.2015.160 · 8.56 Impact Factor

Publication Stats

2k Citations
605.91 Total Impact Points


  • 2011-2015
    • Peking University Health Science Center
      • Department of Biochemistry and Molecular Biology
      Peping, Beijing, China
    • Auburn University
      • Department of Physics
      Auburn, AL, United States
    • Nankai University
      T’ien-ching-shih, Tianjin Shi, China
  • 2003-2015
    • Jilin University
      • College of Life Sciences
      Yung-chi, Jilin Sheng, China
  • 2008-2014
    • Peking University
      • • School of Basic Medical Science
      • • School of Pharmaceutical Sciences
      Peping, Beijing, China
    • 302 Military Hospital of China
      Peping, Beijing, China
  • 2012
    • University of California, Davis
      • Cancer Center
      Davis, California, United States
  • 2006
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
  • 2001-2003
    • Johns Hopkins University
      • Department of Molecular Microbiology and Immunology
      Baltimore, Maryland, United States
  • 2002
    • Johns Hopkins Bloomberg School of Public Health
      • Department of Epidemiology
      Baltimore, Maryland, United States