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1.  βig-h3 Promotes Human Osteosarcoma Cells Metastasis by Interacting with Integrin α2β1 and Activating PI3K Signaling Pathway 
PLoS ONE  2014;9(3):e90220.
Osteosarcoma, the most common primary bone tumor in children and young adolescents, is characterized by local invasion and distant metastasis. But the detailed mechanisms of osteosarcoma metastasis are not well known. In the present study, we found that βig-h3 promotes metastatic potential of human osteosarcoma cells in vitro and in vivo. Furthermore, βig-h3 co-localized with integrin α2β1 in osteosarcoma cells. But βig-h3 did not change integrin α2β1 expression in Saos-2 cells. Interaction of βig-h3 with integrin α2β1 mediates metastasis of human osteosarcoma cells. The second FAS1 domain of βig-h3 but not the first FAS1 domain, the third FAS1 domain or the fourth FAS1 domain mediates human osteosarcoma cells metastasis, which is the α2β1 integrin-interacting domain. We further demonstrated that PI3K/AKT signaling pathway is involved in βig-h3-induced human osteosarcoma cells metastasis process. Together, these results reveal βig-h3 enhances the metastasis potentials of human osteosarcoma cells via integrin α2β1-mediated PI3K/AKT signal pathways. The discovery of βig-h3-mediated pathway helps us to understand the mechanism of human osteosarcoma metastasis and provides evidence for the possibility that βig-h3 can be a potential therapeutic target for osteosarcoma treatment.
doi:10.1371/journal.pone.0090220
PMCID: PMC3942417  PMID: 24595049
2.  Crystal structure of interleukin 17 receptor B SEFIR domain 
Interleukin 17 (IL-17) cytokines play a crucial role in a variety of inflammatory and autoimmune diseases. They signal through heterodimeric receptor complexes consisting of members of IL-17 receptor (IL-17R) family. A unique intracellular signaling domain was identified within all IL-17Rs, termed SEFIR [SEF (similar expression to fibroblast growth factor genes) and IL-17R]. SEFIR is also found in nuclear factor κB (NF-κB) activator 1 (Act1), an E3 ubiquitin ligase, and mediates its recruitment to IL-17Rs. Here we report the structure of the first SEFIR domain from IL-17RB at 1.8Å resolution. SEFIR displays a five-stranded parallel β-sheet that is wrapped by six helices. Site-directed mutagenesis on IL-17RB identified helix αC as being critical for its interaction with Act1 and IL-25 (IL-17E) signaling. Using the current SEFIR structure as a template, the key functional residues in Act1 are also mapped as part of helix αC, which is conserved in IL-17RA and RC, suggesting this helix as a common structural signature for heterotypic SEFIR-SERIR association. On the other hand, helix αB′ is important for homo-dimerization of Act1, implicating a dual ligand-binding model for SEFIR domain, with distinct structural motifs participating in either homotypic or heterotypic interactions. Furthermore, although IL-17RB-SEFIR structure resembles closest to the Toll/Interleukin-1 receptor (TIR) domain of TLR10 with low sequence homology, substantial differences were observed at helices αC, αD and DD′ loop. This study provides the first structural view of the IL-17 receptor intracellular signaling, unraveling the mechanism for the specificity of SEFIR versus TIR domain in their respective signaling pathways.
doi:10.4049/jimmunol.1202922
PMCID: PMC3578156  PMID: 23355738
3.  Oxidative Stress Induces Mitochondrial DNA Damage and Cytotoxicity through Independent Mechanisms in Human Cancer Cells 
BioMed Research International  2012;2013:825065.
Intrinsic oxidative stress through increased production of reactive oxygen species (ROS) is associated with carcinogenic transformation, cell toxicity, and DNA damage. Mitochondrial DNA (mtDNA) is a natural surrogate to oxidative DNA damage. MtDNA damage results in the loss of its supercoiled structure and is readily detectable using a novel, supercoiling-sensitive real-time PCR method. Our studies have demonstrated that mtDNA damage, as measured by DNA strand breaks and copy number depletion, is very sensitive to exogenous H2O2 but independent of endogenous ROS production in both prostate cancer and normal cells. In contrast, aggressive prostate cancer cells exhibit a more than 10-fold sensitivity to H2O2-induced cell toxicity than normal cells, and a cascade of secondary ROS production is a critical determinant to the differential response. We propose a new paradigm to account for different mechanisms governing cellular oxidative stress, cell toxicity, and DNA damage with important ramifications in devising new techniques and strategies in prostate cancer prevention and treatment.
doi:10.1155/2013/825065
PMCID: PMC3591153  PMID: 23509785
4.  A CC′ Loop Decoy Peptide Blocks the Interaction Between Act1 and IL-17RA to Attenuate IL-17- and IL-25-Induced Inflammation 
Science Signaling  2011;4(197):ra72.
Interleukin-17 (IL-17) and IL-25 signaling induce the expression of genes that encode inflammatory factors and they are implicated in the pathology of various inflammatory diseases. Nuclear factor κB (NF-κB) activator 1 (Act1) is an adaptor protein and E3 ubiquitin ligase that is critical for IL-17 and IL-25 signaling, and it is recruited to their receptors through heterotypic interactions between their SEFIR [SEF (similar expression to fibroblast growth factor genes)/IL-17R] domains. Modeling of SEFIR domains has shown their structural similarity with the Toll-IL-1 receptor (TIR) domains of Toll-like receptors (TLRs) and the IL-1R. Whereas the BB′ loop of TIR is required for TIR-TIR interactions, we found that deletion of the BB′ loop from Act1 or IL-17RA (a common subunit of IL-17R and IL-25R) did not affect Act1–IL-17RA interactions. Instead, deletion of the CC′ loop from Act1 or IL-17RA abolished the interaction between Act1 and IL-17RA, suggesting that SEFIR and TIR domains interact in different manners. Surface plasmon resonance measurements showed that a peptide corresponding to the CC′ loop bound directly to IL-17RA. A cell-permeable decoy peptide based on the CC′ loop sequence inhibited IL-17- and IL-25-mediated signaling, and it inhibited IL-17- and IL-25-induced responses in vitro and pulmonary inflammation in vivo. Together, these findings provide the molecular basis for the specificity of SEFIR versus TIR domain interactions and consequent signaling. Moreover, we suggest that the CC′ loop motif of SEFIR domains is a promising target for therapeutic strategies against IL-17- and IL-25-asssociated inflammatory diseases.
doi:10.1126/scisignal.2001843
PMCID: PMC3282585  PMID: 22045852
5.  A shear-based assay for assessing plasma ADAMTS13 activity and inhibitor in patients with thrombotic thrombocytopenic purpura 
Transfusion  2011;51(7):1580-1591.
Background
Severe deficiency of plasma ADAMTS13 activity is a frequent finding in patients with hereditary and acquired thrombotic thrombocytopenic purpura (TTP). To date, plasma ADAMTS13 activity is determined by cleavage of either pre-denatured von Willebrand factor (VWF) or small peptides derived from the VWF-A2 domain. The physiological relevance of the assay results is uncertain.
Methods
We sought to develop a novel shear-based assay to assess plasma ADAMTS13 activity and inhibitor. We also compared this assay with a fluorogenic peptide assay.
Results
We found that an incubation of purified plasma VWF with 0.5-1.0 μl of citrated plasma under constant vortexing at 2,500 rpm for 60 minutes in the presence of 5 mM CaCl2, 1.7 μM ZnCl2 and low concentration of NaCl resulted in the maximal cleavage of VWF. The cleavage product could be separated by a 2.5% agarose gel and detected by Western blotting. The assay revealed that plasma and recombinant ADAMTS13 are highly sensitive to inhibition by zinc and chloride ions. Under the optimal conditions, the shear-based assay appeared to be more sensitive than the guanidine-denaturization assay for determining plasma ADAMTS13 activity.
Conclusions
Our fluid shear-based assay may be useful for investigating basic biological function and regulation of ADAMTS13 metalloprotease. It may also be applicable for assessing plasma ADAMTS13 activity and inhibitors in TTP patients.
doi:10.1111/j.1537-2995.2010.03020.x
PMCID: PMC3168518  PMID: 21251003
6.  Introduction of multiphosphonate ligand to peptide nucleic acid for metal ion conjugation 
Artificial DNA, PNA & XNA  2012;3(2):73-79.
Peptide nucleic acid (PNA) is one of the most widely used synthetic DNA analogs. Conjugation of functional molecules to PNA is very effective to further widen its potential applications. For this purpose, here we report the synthesis of several ligand monomers and introduced them to PNA. These ligand-modified PNAs attract cerium ion and are useful for site-selective DNA hydrolysis. It should be noted that these ligands on PNA are also effective even under the conditions of invasion complex.
doi:10.4161/adna.20727
PMCID: PMC3429533  PMID: 22772037
cerium; DNA; hydrolysis; ligand; metal ion; peptide nucleic acid
7.  Association of SLC38A4 and system A with abnormal fetal birth weight 
In this study, we aimed to explore the correlation between solute carrier family 38 member 4 (SLC38A4) and system A activity in human placentas from pregnancies with abnormal fetal birth weight. We collected placentas from consenting women immediately after their full-term babies were born, with normal, low birth weight or macrosomia, and used real-time PCR and Western blot analysis to detect the levels of SLC38A4 mRNA and protein [also known as sodium-coupled neutral amino acid transport protein 4 (SNAT4)]. Isotope incorporation assay was applied to measure system A activity in the placentas. Compared to the normal birth weight (NBW) group, placentas from the fetal macrosomia (FM) group had significantly increased levels of SLC38A4 mRNA and SNAT4 (both were increased by almost 2-fold; P<0.05), while no significant changes were detected in the placentas from the low birth weight (LBW) group. In addition, system A activity in the placentas from the FM and LBW groups was significantly different from that in the NBW group (1.2±0.20, 0.6±0.14 vs. 1.0±0.18, P<0.05). The data suggest that SNAT4 and system A have a strong association with abnormal fetal birth weight and that they may play a crucial role in fetal growth and development.
doi:10.3892/etm.2011.392
PMCID: PMC3438638  PMID: 22969887
birth weight; solute carrier family 38 member 4; sodium-coupled neutral amino acid transport protein 4; system A
8.  Alterations of hemostatic parameters in the early development of allogeneic hematopoietic stem cell transplantation-related complications 
Annals of Hematology  2011;90(10):1201-1208.
Thrombotic events are common and potentially fatal complications in patients receiving hematopoietic stem cell transplantation (HSCT). Early diagnosis is crucial but remains controversial. In this study, we investigated the early alterations of hemostatic parameters in allogeneic HSCT recipients and determined their potential diagnostic values in transplantation-related thrombotic complications and other post-HSCT events. Results from 107 patients with allogeneic HSCT showed higher levels of plasma plasminogen activator inhibitor-1 (PAI-1), fibrinogen, and tissue-plasminogen activator (t-PA) and a lower level of plasma protein C after transplantation. No change was found for prothrombin time, antithrombin III, d-dimer, and activated partial thromboplastin time following HSCT. Transplantation-related complications (TRCs) in HSCT patients were defined as thrombotic (n = 8), acute graft-versus-host disease (aGVHD, n = 45), and infectious (n = 38). All patients with TRCs, especially the patients with thrombotic complications, presented significant increases in the mean and maximum levels of PAI-1 during the observation period. Similarly, a high maximum t-PA level was found in the thrombotic group. In contrast, apparent lower levels of mean and minimum protein C were observed in the TRC patients, especially in the aGVHD group. Therefore, the hemostatic imbalance in the early phase of HSCT, reflecting prothrombotic state and endothelial injury due to the conditioning therapy or TRCs, might be useful in the differential diagnosis of the thrombotic complication from other TRCs.
doi:10.1007/s00277-011-1273-5
PMCID: PMC3168446  PMID: 21674145
Thrombotic complication; Transplantation-related complications (TRCs); Plasminogen activator inhibitor-1 (PAI-1); Protein C (PC); Hematopoietic stem cell transplantation (HSCT)
9.  Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations 
BMC Medical Genetics  2011;12:6.
Background
Wilson's disease (WND) is a rare autosomal recessive disorder. Here we have evaluated 62 WND cases (58 probands) from the Chinese Han population to expand our knowledge of ATP7B mutations and to more completely characterize WND in China.
Methods
The coding and promoter regions of the ATP7B gene were analyzed by direct sequencing in 62 Chinese patients (58 probands) with WND (male, n = 37; female, n = 25; age range, 2 ~ 61 years old).
Results
Neurologic manifestations were associated with older age at diagnosis (p < 0.0001) and longer diagnostic delay (p < 0.0001). Age at diagnosis was also correlated with urinary copper concentration (r = 0.58, p < 0.001). Forty different mutations, including 14 novel mutations, were identified in these patients. Common mutations included p.Arg778Leu (31.9%) and p.Pro992Leu (11.2%). Homozygous p.Arg778Leu and nonsense mutation/frameshift mutations were more often associated with primary hepatic manifestations (p = 0.0286 and p = 0.0383, respectively) and higher alanine transaminase levels at diagnosis (p = 0.0361 and p = 0.0047, respectively). Nonsense mutation/frameshift mutations were also associated with lower serum ceruloplasmin (p = 0.0065).
Conclusions
We identified 14 novel mutations and found that the spectrum of mutations of ATP7B in China is quite distinct from that of Western countries. The mutation type plays a role in predicting clinical manifestations. Genetic testing is a valuable tool to detect WND in young children, especially in patients younger than 8 years old. Four exons (8, 12, 13, and 16) and two mutations (p.Arg778Leu, p.Pro992Leu) should be considered high priority for cost-effective testing in China.
doi:10.1186/1471-2350-12-6
PMCID: PMC3025937  PMID: 21219664
10.  Theoretical Investigations into Self-Organized Ordered Metallic Semi-Clusters Arrays on Metallic Substrate 
Nanoscale Research Letters  2010;5(6):1020-1026.
Using the energy minimization calculations based on an interfacial potential and a first-principles total energy method, respectively, we show that (2 × 2)/(3 × 3) Pb/Cu(111) system is a stable structure among all the [(n − 1) × (n − 1)]/(n × n) Pb/Cu(111) (n = 2, 3,…, 12) structures. The electronic structure calculations indicate that self-organized ordered Pb semi-clusters arrays are formed on the first Pb monolayer of (2 × 2)/(3 × 3) Pb/Cu(111), which is due to a strain-release effect induced by the inherent misfits. The Pb semi-clusters structure can generate selective adsorption of atoms of semiconductor materials (e.g., Ge) around the semi-clusters, therefore, can be used as a template for the growth of nanoscale structures with a very short periodic length (7.67 Å).
doi:10.1007/s11671-010-9595-0
PMCID: PMC2893967  PMID: 20672088
Self-organized; Template; Interface potential; Molecular dynamics; First-principles calculation
11.  Theoretical Investigations into Self-Organized Ordered Metallic Semi-Clusters Arrays on Metallic Substrate 
Nanoscale Research Letters  2010;5(6):1020-1026.
Using the energy minimization calculations based on an interfacial potential and a first-principles total energy method, respectively, we show that (2 × 2)/(3 × 3) Pb/Cu(111) system is a stable structure among all the [(n − 1) × (n − 1)]/(n × n) Pb/Cu(111) (n = 2, 3,…, 12) structures. The electronic structure calculations indicate that self-organized ordered Pb semi-clusters arrays are formed on the first Pb monolayer of (2 × 2)/(3 × 3) Pb/Cu(111), which is due to a strain-release effect induced by the inherent misfits. The Pb semi-clusters structure can generate selective adsorption of atoms of semiconductor materials (e.g., Ge) around the semi-clusters, therefore, can be used as a template for the growth of nanoscale structures with a very short periodic length (7.67 Å).
doi:10.1007/s11671-010-9595-0
PMCID: PMC2893967  PMID: 20672088
Self-organized; Template; Interface potential; Molecular dynamics; First-principles calculation
12.  Protective Immunity Elicited by a Divalent DNA Vaccine Encoding Both the L7/L12 and Omp16 Genes of Brucella abortus in BALB/c Mice  
Infection and Immunity  2006;74(5):2734-2741.
This study was designed to evaluate the immunogenicity and the protective efficacy of a divalent fusion DNA vaccine encoding both the Brucella abortus L7/L12 protein (ribosomal protein) and Omp16 protein (outer membrane lipoprotein), designated pcDNA3.1-L7/L12-Omp16. Intramuscular injection of this divalent DNA vaccine into BALB/c mice elicited markedly both humoral and cellular immune responses. The specific antibodies exhibited a dominance of immunoglobulin G2a (IgG2a) over IgG1. In addition, the dual-gene DNA vaccine elicited a strong T-cell proliferative response and induced a large amount of gamma interferon-producing T cells upon restimulation in vitro with recombinant fusion protein L7/L12-Omp16, suggesting the induction of a typical T-helper-1-dominated immune response in vivo. This divalent DNA vaccine could also induce a significant level of protection against challenge with the virulent strain B. abortus 544 in BALB/c mice. Furthermore, the protection level induced by the divalent DNA vaccine was significantly higher than that induced by the univalent DNA vaccines pcDNA3.1-L7/L12 or pcDNA3.1-Omp16. Taken together, the results of this study verify for the first time that the Omp16 gene can be a candidate target for a DNA vaccine against brucellosis. Additionally, a divalent genetic vaccine based on the L7/L12 and Omp16 genes can elicit a stronger cellular immune response and better immunoprotection than the relevant univalent vaccines can.
doi:10.1128/IAI.74.5.2734-2741.2006
PMCID: PMC1459688  PMID: 16622210

Results 1-12 (12)