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1.  Exenatide can inhibit calcification of human VSMCs through the NF-kappaB/RANKL signaling pathway 
Cardiovascular Diabetology  2014;13(1):153.
Arterial calcification is an important pathological change of diabetic vascular complication. Osteoblastic differentiation of vascular smooth muscle cells (VSMCs) plays an important cytopathologic role in arterial calcification. The glucagon-like peptide-1 receptor agonists (GLP-1RA), a novel type of antidiabetic drugs, exert cardioprotective effects through the GLP-1 receptor (GLP-1R). However, the question of whether or not GLP-1RA regulates osteoblastic differentiation and calcification of VSMCs has not been answered, and the associated molecular mechanisms have not been examined.
Calcifying VSMCs (CVSMCs) were isolated from cultured human arterial smooth muscle cells through limiting dilution and cloning. The extent of matrix mineralization was measured by Alizarin Red S staining. Protein expression and phosphorylation were detected by Western blot. Gene expression of receptor activator of nuclear factor-κB ligand (RANKL) was silenced by small interference RNA (siRNA).
Exenatide, an agonist of GLP-1 receptor, attenuated β-glycerol phosphate (β-GP) induced osteoblastic differentiation and calcification of human CVSMCs in a dose- and time-dependent manner. RANKL siRNA also inhibited osteoblastic differentiation and calcification. Exenatide decreased the expression of RANKL in a dose-dependent manner. 1,25 vitD3 (an activator of RANKL) upregulated, whereas BAY11-7082 (an inhibitor of NF-κB) downregulated RANKL, alkaline phosphatase (ALP), osteocalcin (OC), and core binding factor α1 (Runx2) protein levels and reduced mineralization in human CVSMCs. Exenatide decreased p-NF-κB and increased p-AMPKα levels in human CVSMCs 48 h after treatment. Significant decrease in p-NF-κB (p-Ser276, p-Ser536) level was observed in cells treated with exenatide or exenatide + BAY11-7082.
GLP-1RA exenatide can inhibit human VSMCs calcification through NF-κB/RANKL signaling.
PMCID: PMC4241215  PMID: 25407893
Arterial calcification; Vascular smooth muscle cells; Osteoblastic differentiation; Glucagon-like peptide-1; Diabetes
2.  Comparison of Insulators and Promoters for Expression of the Wiskott–Aldrich Syndrome Protein Using Lentiviral Vectors 
Gene therapy for the treatment of Wiskott–Aldrich syndrome (WAS) presents an alternative to the current use of allogeneic bone marrow transplantation. We describe the development of a self-inactivating lentiviral vector containing chromatin insulators for treatment of WAS and compare a gammaretroviral (MND), human cellular (EF1α), and the human WASp gene promoter for expression patterns in vivo during murine hematopoiesis using the green fluorescent protein (GFP) marker. Compared with the EF1α and the WASp promoters, expression from the MND promoter in mouse transplant recipients was much higher in all lineages examined. Importantly, there was sustained expression in the platelets of secondary recipient animals, necessary to correct the thrombocytopenia defect in WAS patients. Analysis of WAS protein expression in transduced human EBV-immortalized B-cells and transduced patient peripheral blood mononuclear cells also demonstrated stronger expression per copy from the MND promoter compared with the other promoters. In addition, when analyzed in an LM02 activation assay, the addition of an insulator to MND-promoter-containing constructs reduced transactivation of the LM02 gene. We propose a clinical trial design in which cytokine-mobilized, autologous, transduced CD34+ cells are administered after myelosuppression.
Koldej and colleagues perform preclinical evaluation of three promoters in a self-inactivating lentiviral vector being developed for ex vivo gene therapy of Wiskott Aldrich Syndrome (WAS). They demonstrate that a gammaretroviral promoter drives robust green fluorescent protein expression in multiple hematopoietic lineages in a mouse bone marrow transplant model, as well as significant WAS protein expression in patient peripheral blood cells. They further demonstrate that inclusion of insulator sequences can effectively abrogate insertional activation of the LMO2 gene, which has previously been found to drive malignant transformation of retroviral vector–transduced cells in human trials.
PMCID: PMC4003467  PMID: 23786330
3.  LiFePO4 microcrystals as an efficient heterogeneous Fenton-like catalyst in degradation of rhodamine 6G 
Nanoscale Research Letters  2014;9(1):276.
We present a novel heterogeneous Fenton-like catalyst of LiFePO4 (LFP). LFP has been widely used as an electrode material of a lithium ion battery, but we observed that commercial LFP (LFP-C) could act as a good Fenton-like catalyst to decompose rhodamine 6G. The catalytic activity of LFP-C microparticles was much higher than a popular catalyst, magnetite nanoparticles. Furthermore, we found that the catalytic activity of LFP-C could be further increased by increasing the specific surface area. The reaction rate constant of the hydrothermally synthesized LFP microcrystals (LFP-H) is at least 18 times higher than that of magnetite nanoparticles even though the particle size of LFP is far larger than magnetite nanoparticles. The LFP catalysts also exhibited a good recycling behavior and high stability under an oxidizing environment. The effects of the experimental parameters such as the concentration of the catalysts, pH, and the concentration of hydrogen peroxide on the catalytic activity of LFP were also analyzed.
PMCID: PMC4051962  PMID: 24948896
Fenton-like catalyst; LiFePO4; Rhodamine 6G; Advanced oxidation
4.  Vitamin D Binding Protein Affects the Correlation of 25(OH)D and Frailty in the Older Men 
Vitamin D binding protein (DBP) may alter the biologic activity of 25-hydroxyvitamin D [25(OH)D]. The objective of our present study was to determine the joint effect of serum 25(OH)D and DBP on the risk of frailty. Five hundred sixteen male participants aged 70 years or older were recruited in Changsha city and its surrounding area in Hunan province of China. Frailty was defined as the presence of at least three of the five following criteria: weakness, low physical activity, slow walking speed, exhaustion, and weight loss. Multivariate linear regression analysis was performed to assess the relationship between 25(OH)D and DBP levels. Odds ratios (ORs) for frailty were evaluated across quartiles of 25(OH)D and DBP levels, adjusted age, education, and body mass index. The results showed that participants in the lowest quartile of 25(OH)D and the highest quartile of DBP levels, the lowest quartile of 25(OH)D and the lowest quartile of DBP levels, and those in the the lower quartile of 25(OH)D and lowest quartile of DBP levels had significantly higher OR of being frail compared with those in the highest quartile of 25(OH)D and lowest quartile of DBP, with OR of 3.18 (95% CI: 1.46–4.56, P < 0.05), 2.63 (95% CI: 1.31–3.68, P < 0.01), and 2.52 (95% CI: 1.22–3.52, P < 0.05), respectively. The results indicate that the joint effect of serum 25(OH)D and DBP levels is associated with the risk of frailty, and serum DBP levels affects 25(OH)D-frailty relationship in the older men.
PMCID: PMC4005149  PMID: 24822065
5.  The Geometry of the Bone Structure Associated with Total Hip Arthroplasty 
PLoS ONE  2014;9(3):e91058.
Close adaptation of the prosthesis to the bone is the key to achieving optimal stability and fixation for total hip arthroplasty (THA). However, there have been no adequate studies of bone morphology, especially in different races. The aim of this study was to analyze the geometry of the acetabulum and proximal femur of people from South China, based on three-dimensional reconstruction, and to detect differences between different population subsets. CT scans were performed on 80 healthy volunteers (160 hips) from South China, comprising 40 males (80 hips) and 40 females (80 hips). The images were imported into Mimics 10.01 to perform 3D reconstruction. THA-associated anatomical parameters were measured and compared with other published data. In comparison with published data, it seemed that people from South China have smaller acetabular abduction angle, larger acetabular supro-inferior diameter, larger neck-shaft angle, smaller offset, thinner femoral shaft and more proximal isthmus, which needed to be further confirmed. There were significant differences between the genders in most parameters. As significant differences in canal flare index (CFI) and distal canal flare index (DCFI) were found between genders, it was concluded the most significant differences lay in the isthmus of the femur. Among the femora, according to Noble’s classification we identified more normal types and fewer stovepipe and champagne-flute types than expected from the literature, indicating that uncemented prostheses would be suitable for most people from South China. Our findings reveal that simply choosing the smallest of a series of prostheses would not necessarily provide a good fit, due to the different trends from the proximal to the distal part of the femur. Significant variation exists in THA-associated anatomy between genders and population subsets. It is therefore imperative that each patient receives individual consideration rather than assuming all patients have the same anatomy, especially for different races.
PMCID: PMC3946655  PMID: 24608343
6.  Effects of Low-Dose Testosterone Undecanoate Treatment on Bone Mineral Density and Bone Turnover Markers in Elderly Male Osteoporosis with Low Serum Testosterone 
This prospective 2-year, single-center, randomized, placebo-controlled, open-label clinical trial was performed to evaluate the efficacy of low-dose testosterone undecanoate (TU) treatment on bone mineral density (BMD) and biochemical markers of bone turnover in elderly male osteoporosis with low serum testosterone. A total of 186 elderly male osteoporosis patients with low serum testosterone were randomized into three groups: low-dose TU (20 mg, per day), standard-dose TU (40 mg, per day), and placebo group with a 24-month followup. Since the 6th month in standard-dose TU group or since the 12th month followup in low-dose TU group and throughout the study, lumbar spine and femoral neck BMD and serum levels of free testosterone, estradiol, and bone alkaline phosphatase significantly increased. There were no significant differences between groups of low-dose TU and standard dose TU in the percentage of changes of these data since the 18th month followup and throughout the study. No side effects on prostate glands including prostate specific antigen were found. In conclusion, low-dose TU (20 mg, per day) may be a cost effective and safe protocol for treating elderly male osteoporosis with low serum testosterone.
PMCID: PMC3603196  PMID: 23533404
7.  Potent Inhibition of Angiogenesis by the IGF-1 Receptor-Targeting Antibody SCH717454 is Reversed by IGF-2 
Molecular cancer therapeutics  2011;11(3):649-659.
Previously, we reported that a predominant action of an IGF-1R-targeted antibody was through inhibiting tumor-derived VEGF, and indirectly, angiogenesis. Here we examined the direct anti-angiogenic activity of the IGF-1R-targeted antibody SCH717454 that inhibits ligand-receptor binding, and the mechanism by which tumors circumvent its anti-angiogenic activity. Inhibition of ligand stimulated activation of IGF-1R, insulin receptor (IN-R) or downstream signaling (phosphorylation of Akt [Ser473]) was determined by receptor-specific immunoprecipitation and immunoblotting. Inhibition of angiogenesis was determined by proliferation and tube formation using human umbilical vein endothelial cells (HUVECs) in vitro and in Matrigel plugs implanted in mice. SCH717454 blocked IGF-1 but not IGF-2 stimulated phosphorylation of Akt in sarcoma cells. Immunoprecipitation using anti-IGF-1R and anti-IN-R antibodies revealed that SCH717454 equally blocked IGF-1 and IGF-2 stimulated IGF-1R phosphorylation, but not IGF-2 stimulated phosphorylation of IN-R. SCH717454 completely blocked VEGF-stimulated proliferation and tube formation of HUVECs, but exogenous IGF-2 and insulin circumvented these inhibitory effects. Co-culture of HUVECs with IGF-2-secreting tumor cells completely abrogated SCH717454 inhibition of VEGF-stimulated HUVEC tube formation. In mice SCH717454 inhibited angiogenesis in VEGF-infused Matrigel plugs, but had no inhibitory activity when plugs contained both VEGF+IGF-2. These results reveal for the first time, a role for IGF-1R signaling in VEGF-mediated angiogenesis in vitro and indicate direct anti-angiogenic activity of SCH717454. Both in vitro and in vivo IGF-2 circumvented these effects through IN-R signaling. Many childhood cancers secrete IGF-2, suggesting that tumor-derived IGF-2 in the microenvironment maintains angiogenesis in the presence of IGF-1R-targeted antibodies allowing tumor progression.
PMCID: PMC3421238  PMID: 22188815
insulin-like growth factors; sarcomas; IGF-1R-targeted antibodies; angiogenesis
8.  Opposite Role of Kindlin-1 and Kindlin-2 in Lung Cancers 
PLoS ONE  2012;7(11):e50313.
Lung cancer is highly heterogenous and is composed of various subtypes that are in diverse differential stages. The newly identified integrin-interacting proteins Kindlin-1 and Kindlin-2 are the activators of transmembrane receptor integrins that play important roles in cancer progression. In this report we present the expression profiles of Kindlin-1 and Kindlin-2 in lung cancers using patient specimens and established their correlation with lung cancer progression. We found that Kindlin-1 was expressed in epithelia-derived non-small-cell lung cancer, especially in squamous cell lung cancer but expressed at low levels in poorly differentiated large cell lung cancer. However, Kindlin-2 was highly expressed in large cell lung cancer. Both Kindlin-1 and Kindlin-2 were found not expressed or expressed at very low levels in neuroendocrine-derived small cell lung cancer. Importantly, the Kindlin-1 expression level was positively correlated with the differentiation of squamous cell lung cancer. Surprisingly, we found that the very homologous Kindlin family proteins, Kindlin-1 and Kindlin-2, displayed counteracting functional roles in lung cancer cells. Ectopic expression of Kindlin-1 in non-small-cell lung cancer cells inhibited in vitro cell migration and in vivo tumor growth, while Kindlin-2 promoted these functions. Mechanistically, Kindlin-1 prohibited epithelail to mesenchymal transition in non-small-cell lung cancer cells, while Kindlin-2 enhanced epithelail to mesenchymal transition in these cells. Taken together, we demonstrated that Kindlin-1 and Kindlin-2 differentially regulate lung cancer cell progression. Further, the expression levels of Kindlin-1 might be potentially used as a marker for lung cancer differentiation and targeting Kindlin-2 might block the invasive growth of large cell lung cancer.
PMCID: PMC3510225  PMID: 23209705
9.  Synergism and Rules from Combination of Baicalin, Jasminoidin and Desoxycholic acid in Refined Qing Kai Ling for Treat Ischemic Stroke Mice Model 
PLoS ONE  2012;7(9):e45811.
Refined Qing-Kai-Ling (QKL), a modified Chinese medicine, consists of three main ingredients (Baicalin, Jasminoidin and Desoxycholic acid), plays a synergistic effect on the treatment of the acute stage of ischemic stroke. However, the rules of the combination and synergism are still unknown. Based on the ischemic stroke mice model, all different kinds of combination of Baicalin, Jasminoidin, and Desoxycholic acid were investigated by the methods of neurological examination, microarray, and genomics analysis. As a result, it confirmed that the combination of three drugs offered a better therapeutical effect on ischemic stroke than monotherapy of each drug. Additionally, we used Ingenuity pathway Analysis (IPA) and principal component analysis (PCA) to extract the dominant information of expression changes in 373 ischemia-related genes. The results suggested that 5 principal components (PC1-5) could account for more than 95% energy in the gene data. Moreover, 3 clusters (PC1, PC2+PC5, and PC3+PC4) were addressed with cluster analysis. Furthermore, we matched PCs on the drug-target networks, the findings demonstrated that Baicalin related with PC1 that played the leading role in the combination; Jasminoidin related with PC2+PC5 that played a compensatory role; while Desoxycholic acid had the least performance alone which could relate with PC3+PC4 that played a compatible role. These manifestations were accorded with the principle of herbal formulae of Traditional Chinese Medicine (TCM), emperor-minister-adjuvant-courier. In conclusion, we firstly provided scientific evidence to the classic theory of TCM formulae, an initiating holistic viewpoint of combination therapy of TCM. This study also illustrated that PCA might be an applicable method to analyze the complicated data of drug combination.
PMCID: PMC3458908  PMID: 23049867
10.  Emergence and Continuous Evolution of Genotype 1E Rubella Viruses in China 
Journal of Clinical Microbiology  2012;50(2):353-363.
In China, rubella vaccination was introduced into the national immunization program in 2008, and a rubella epidemic occurred in the same year. In order to know whether changes in the genotypic distribution of rubella viruses have occurred in the postvaccination era, we investigate in detail the epidemiological profile of rubella in China and estimate the evolutionary rate, molecular clock phylogeny, and demographic history of the predominant rubella virus genotypes circulating in China using Bayesian Markov chain Monte Carlo phylodynamic analyses. 1E was found to be the predominant rubella virus genotype since its initial isolation in China in 2001, and no genotypic shift has occurred since then. The results suggest that the global 1E genotype may have diverged in 1995 and that it has evolved at a mutation rate of 1.65 × 10−3 per site per year. The Chinese 1E rubella virus isolates were grouped into either cluster 1 or cluster 2, which likely originated in 1997 and 2006, respectively. Cluster 1 viruses were found in all provinces examined in this study and had a mutation rate of 1.90 × 10−3 per site per year. The effective number of infections remained constant until 2007, and along with the introduction of rubella vaccine into the national immunization program, although the circulation of cluster 1 viruses has not been interrupted, some viral lineages have disappeared, and the epidemic started a decline that led to a decrease in the effective population size. Cluster 2 viruses were found only in Hainan Province, likely because of importation.
PMCID: PMC3264136  PMID: 22162559
11.  Poly[[aqua­(μ5-3,4,5,6-tetra­carb­oxy­cyclo­hexane-1,2-dicarboxyl­ato)strontium] monohydrate] 
In the title compound, {[Sr(C12H10O12)(H2O)]·H2O}n, the SrII ion is coordinated by six O atoms of five symmetry-related 3,4,5,6-tetra­carb­oxy­cyclo­hexane-1,2-dicarboxyl­ate ligands and one water mol­ecule in a slightly distorted monocapped trigonal–prismatic environment. The ligands bridge the SrII ions, forming a two-dimensional structure. In the crystal, O—H⋯O hydrogen bonds further connect the structure into a three-dimensional network. The H atoms of two of the carboxyl groups were refined as half-occupancy.
PMCID: PMC3238780  PMID: 22199657
12.  Poly[tetra­aqua­(μ8-butane-1,2,3,4-tetra­carboxyl­ato)distrontium] 
In the title compound, [Sr2(C8H6O8)(H2O)4)]n, the SrII ion is coordinated by six O atoms of four symmetry-related ligands and two water mol­ecules in a distorted bicapped trigonal–prismatic environment. The butane-1,2,3,4-tetra­carboxyl­ate ligands lie on inversion centers and bridge SrII ions, forming a three-dimensional network. Within the three-dimensional structure, there are O—H⋯O hydrogen bonds involving the water mol­ecules and carboxyl­ate O atoms.
PMCID: PMC3238625  PMID: 22199516
13.  Poly[tetra­kis­(μ-benzene-1,2-dicarboxyl­ato)di-μ-formato-penta­strontium(II)] 
The asymmetric unit of the title complex, [Sr5(C8H4O4)4(HCO2)2]n, contains three independent SrII ions, one of which is located on an inversion center. In the crystal, the SrII ions (coordination numbers 8, 9 and 12) are connected by two crystallographically distinct benzene-1,2-dicarboxyl­ate ligands and one formate ligand, forming a two-dimensional polymer parallel to (001).
PMCID: PMC3238585  PMID: 22199476
14.  1-[4-(4-Chloro­but­oxy)-2-hy­droxy­phen­yl]ethanone 
In the title compound, C12H15ClO3, the eth­oxy group is nearly coplanar with the benzene ring, making a dihedral angle of 9.03 (4)°, and is involved in an intra­molecular O—H⋯O hydrogen bond to the neighbouring hy­droxy group.
PMCID: PMC3051656  PMID: 21523123
15.  α-Tocopheryl succinate induces apoptosis in erbB2-expressing breast cancer cell via NF-κB pathway 
Acta Pharmacologica Sinica  2010;31(12):1604-1610.
To study the molecular mechanisms underlying α-tocopheryl succinate (α-TOS)-induced apoptosis in erbB2-positive breast cancer cells and to determine whether α-TOS and the human recombinant TNF-related apoptosis-inducing ligand (hrTRAIL) act synergically to induce cell death of erbB2-expressing breast cancer cells.
The annexin V binding method was used to measure apoptosis induced by α-TOS and/or hrTRAIL. RT-PCR and Western blotting were performed to detect gene and protein expression. A colorimetric assay was performed to detect caspase activity. The TransAMTM NF-κB p65 kit was used to assess NF-κB activation.
α-TOS (100 μmol/L) significantly inhibited NF-κB nuclear translocation in erbB2-expressing breast cancer cells; this inhibition is expected to result in the inactivation of NF-κB. α-TOS (50 and 100 μmol/L) inhibited the expression of Flice-like inhibitory protein (FLIP) and cellular inhibitor of apoptosis protein 1 (c-IAP1) in erbB2-positive cells. α-TOS (100 μmol/L) inhibited Akt activation and augmented the activity of caspase 3 and caspase 8 in breast cancer cells expressing erbB2. α-TOS (50 μmol/L) and hrTRAIL (30 mg/mL) acted synergically to induce apoptosis in breast cancer cells. α-TOS also decreased the hrTRAIL-induced transient activation of NF-κB .
Our results suggest that α-TOS mediates the apoptosis of erbB2-positive breast cancer cells and acts synergically with hrTRAIL via the NF-κB pathway.
PMCID: PMC4002948  PMID: 21127496
erbB2; α-TOS; breast cancer; NF-κB; apoptosis; hrTRAIL
16.  Rubella Virus Genotypes in the People's Republic of China between 1979 and 2007: a Shift in Endemic Viruses during the 2001 Rubella Epidemic▿ † 
Journal of Clinical Microbiology  2010;48(5):1775-1781.
The incidence of rubella cases in China from 1991 to 2007 was reviewed, and the nucleotide sequences from 123 rubella viruses collected during 1999 to 2007 and 4 viral sequences previously reported from 1979 to 1984 were phylogenetically analyzed. Rubella vaccination was not included in national immunization programs in China before 2007. Changes in endemic viruses were compared with incidences of rubella epidemics. The results showed that rubella epidemics occur approximately every 6 to 8 years (1993/1994, 2001, and 2007), and a shift of disease burden to susceptible young adults was observed. The Chinese rubella virus sequences were categorized into 5 of the 13 rubella virus genotypes, 1a, 1E, 1F, 2A, and 2B; cocirculations of these different genotypes were found in China. In Anhui province, a shift in the predominant genotype from 1F and 2B to 1E coincided with the 2001 rubella epidemic. This shift may have occurred throughout China during 2001 to 2007. This study investigated the genotype distribution of rubella viruses in China over a 28-year period to establish an important genetic baseline in China during its prevaccination era.
PMCID: PMC2863877  PMID: 20351211
17.  Negative Regulation of ASK1 by p21Cip1 Involves a Small Domain That Includes Serine 98 That Is Phosphorylated by ASK1 In Vivo▿ †  
Molecular and Cellular Biology  2007;27(9):3530-3541.
The cyclin-dependent kinase inhibitor p21Cip1 regulates multiple cellular functions and protects cells from genotoxic and other cellular stresses. Activation of apoptosis signal-regulating kinase 1 (ASK1) induced by inhibition of mTOR signaling leads to sustained phospho-c-Jun that is suppressed in cells with functional p53 or by forced expression of p21Cip1. Here we show that small deletions of p21Cip1 around S98 abrogate its association with ASK1 but do not affect binding to Cdk1, hence distinguishing between the cell cycle-regulating functions of p21Cip1 and its ability to suppress activation of the ASK1/Jun N-terminal protein kinase (JNK) pathway. p21Cip1 is phosphorylated in vitro by both ASK1 and JNK1 at S98. In vivo phosphorylation of p21Cip1, predominantly carried out by ASK1, is associated with binding to ASK1 and inactivation of ASK1 kinase function. Binding of p21Cip1 to ASK1 requires ASK1 kinase function and may involve phosphorylation of S98.
PMCID: PMC1899956  PMID: 17325029
18.  Multiple organ infection and the pathogenesis of SARS 
After >8,000 infections and >700 deaths worldwide, the pathogenesis of the new infectious disease, severe acute respiratory syndrome (SARS), remains poorly understood. We investigated 18 autopsies of patients who had suspected SARS; 8 cases were confirmed as SARS. We evaluated white blood cells from 22 confirmed SARS patients at various stages of the disease. T lymphocyte counts in 65 confirmed and 35 misdiagnosed SARS cases also were analyzed retrospectively. SARS viral particles and genomic sequence were detected in a large number of circulating lymphocytes, monocytes, and lymphoid tissues, as well as in the epithelial cells of the respiratory tract, the mucosa of the intestine, the epithelium of the renal distal tubules, the neurons of the brain, and macrophages in different organs. SARS virus seemed to be capable of infecting multiple cell types in several organs; immune cells and pulmonary epithelium were identified as the main sites of injury. A comprehensive theory of pathogenesis is proposed for SARS with immune and lung damage as key features.
PMCID: PMC2213088  PMID: 16043521

Results 1-18 (18)