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1.  Kinetic analysis of the immunity in a pregnant patient infected with avian influenza H7N9 
Background: Human infection with avian influenza A H7N9 has emerged in China since February, 2013. The immunologic changes in pregnant women infected with H7N9 are not known. Objective: To report the clinical data and kinetic changes of immunity in a pregnant woman infected with H7N9 virus in Zhenjiang, Jiangsu, China. Methods: The clinical data were collected and immunity status was monitored in this patient. Results: H7N9 virus became undetectable in sputum from 14 days since onset of symptoms after effective antiviral therapy with oseltamivir and symptomatic/supporting treatments. The symptoms and signs in this patient gradually improved from 15 days since onset of symptoms. Peripheral lymphocytes initially decreased and gradually increased. The percentage of CD4+ T cells increased since 16 days after onset of symptoms. The kinetic changes of cytokines including IFN-γ, IFN-α, TNF-α, IL-10 and TGF-β1 matched the development and recovery of illness. Her family members, including her parents exposed to H7N9 positive materials in poultry market, were H7N9 negative. Conclusions: Our results indicate that pregnant women are susceptible to H7N9 virus and H7N9 infection in pregnant women is curable without significant impact on fetus. Kinetic changes of pro-inflammatory and anti-inflammatory cytokines play a role in the pathogenesis and clinical outcome in the pregnant patient with H7N9 infection.
PMCID: PMC4132142  PMID: 25126178
H7N9; cytokine; pregnancy
2.  Murine Th9 cells promote the survival of myeloid dendritic cells in cancer immunotherapy 
Dendritic cells (DCs) are professional antigen-presenting cells to initiate immune responses, and DC survival time is important for affecting the strength of T-cell responses. Interleukin (IL)-9-producing T-helper (Th)-9 cells play an important role in anti-tumor immunity. However, it is unclear how Th9 cells communicate with DCs. In this study, we investigated whether murine Th9 cells affected the survival of myeloid DCs. DCs derived from C57BL/6 mice bone marrow were cocultured with Th9 cells from OT-II mice using Transwell, and the survival of DCs was examined. DCs cocultured with Th9 cells had longer survival and fewer apoptotic cells than DCs cultured alone in vitro. In melanoma B16-OVA tumor-bearing mice, DCs conditioned by Th9 cells lived longer and induced stronger anti-tumor response than control DCs did in vivo. Mechanistic studies revealed that IL-3 but not IL-9 secreted by Th9 cells was responsible for the prolonged survival of DCs. IL-3 upregulated the expression of antiapoptotic protein Bcl-xL and activated p38, ERK and STAT5 signaling pathways in DCs. Taken together, our data provide the first evidence that Th9 cells can promote the survival of DCs through IL-3, and will be helpful for designing Th9 cell immunotherapy and more effective DC vaccine for human cancers.
PMCID: PMC4200484  PMID: 24841535
Th9 cells; Dendritic Cells; survival; IL-3; cancer immunotherapy
3.  Rap2B promotes proliferation, migration, and invasion of human breast cancer through calcium-related ERK1/2 signaling pathway 
Scientific Reports  2015;5:12363.
Rap2B, a member of GTP-binding proteins, is widely upregulated in many types of tumors and promotes migration and invasion of human suprarenal epithelioma. However, the function of Rap2B in breast cancer is unknown. Expression of Rap2B was examined in breast cancer cell lines and human normal breast cell line using Western blot analysis. Using the CCK-8 cell proliferation assay, cell cycle analysis, and transwell migration assay, we also elucidated the role of Rap2B in breast cancer cell proliferation, migration, and invasion. Results showed that the expression of Rap2B is higher in tumor cells than in normal cells. Flow cytometry and Western blot analysis revealed that Rap2B elevates the intracellular calcium level and further promotes extracellular signal-related kinase (ERK) 1/2 phosphorylation. By contrast, calcium chelator BAPTM/AM and MEK inhibitor (U0126) can reverse Rap2B-induced ERK1/2 phosphorylation. Furthermore, Rap2B knockdown inhibits cell proliferation, migration, and invasion abilities via calcium related-ERK1/2 signaling. In addition, overexpression of Rap2B promotes cell proliferation, migration and invasion abilities, which could be neutralized by BAPTM/AM and U0126. Taken together, these findings shed light on Rap2B as a therapeutic target for breast cancer.
PMCID: PMC4512009  PMID: 26201295
4.  Diffuse anterior retinoblastoma: current concepts 
OncoTargets and therapy  2015;8:1815-1821.
Diffuse anterior retinoblastoma is a rare variant of retinoblastoma seeding in the area of the vitreous base and anterior chamber. Patients with diffuse anterior retinoblastoma are older than those with the classical types, with the mean age being 6.1 years. The original cells of diffuse anterior retinoblastoma are supposed to be cone precursor. Patients most commonly present with pseudouveitis, pseudohypopyon, and increased intraocular pressure. The retina under fundus examination is likely to be normal, and the clinical features mimic the inflammation progress, which can often lead to misdiagnosis. The published diffuse anterior retinoblastoma cases were diagnosed after fine-needle aspiration biopsy running the potential risk of inducing metastasis. The most common treatment for diffuse anterior retinoblastoma is enucleation followed by systematic chemotherapy according to the patient’s presentation and clinical course. This review summarizes the recent advances in etiology (including tumorigenesis and cell origin), pathology, diagnosis, differential diagnosis, and new treatment. The challenges of early diagnosis and prospects are also discussed.
PMCID: PMC4516192  PMID: 26229489
pathology; microenvironment; treatment; diagnosis
5.  Relative Contributions of Spectral and Temporal Cues to Korean Phoneme Recognition 
PLoS ONE  2015;10(7):e0131807.
This study was aimed to evaluate the relative contributions of spectral and temporal information to Korean phoneme recognition and to compare them with those to English phoneme recognition. Eleven normal-hearing Korean-speaking listeners participated in the study. Korean phonemes, including 18 consonants in a /Ca/ format and 17 vowels in a /hVd/ format, were processed through a noise vocoder. The spectral information was controlled by varying the number of channels (1, 2, 3, 4, 6, 8, 12, and 16) whereas the temporal information was controlled by varying the lowpass cutoff frequency of the envelope extractor (1 to 512 Hz in octave steps). A total of 80 vocoder conditions (8 numbers of channels × 10 lowpass cutoff frequencies) were presented to listeners for phoneme recognition. While vowel recognition depended on the spectral cues predominantly, a tradeoff between the spectral and temporal information was evident for consonant recognition. The overall consonant recognition was dramatically lower than that of English consonant recognition under similar vocoder conditions. The complexity of the Korean consonant repertoire, the three-way distinction of stops in particular, hinders recognition of vocoder-processed phonemes.
PMCID: PMC4498788  PMID: 26162017
6.  Effect of transient scrotal hyperthermia on sperm parameters, seminal plasma biochemical markers, and oxidative stress in men 
Asian Journal of Andrology  2015;17(4):668-675.
In this experimental prospective study, we aimed to analyze the effect of transient scrotal hyperthermia on the male reproductive organs, from the perspective of sperm parameters, semen plasma biochemical markers, and oxidative stress, to evaluate whether different frequencies of heat exposure cause different degrees of damage to spermatogenesis. Two groups of volunteers (10 per group) received testicular warming in a 43°C water bath 10 times, for 30 min each time: group 1: 10 consecutive days; group 2: once every 3 days. Sperm parameters, epididymis and accessory sex gland function, semen plasma oxidative stress and serum sex hormones were tested before treatment and in the 16-week recovery period after treatment. At last, we found an obvious reversible decrease in sperm concentration (P = 0.005 for Group 1 and P= 0.008 for Group 2 when the minimums were compared with baseline levels, the same below), motility (P = 0.009 and 0.021, respectively), the hypoosmotic swelling test score (P = 0.007 and 0.008, respectively), total acrosin activity (P = 0.018 and 0.009, respectively), and an increase in the seminal plasma malondialdehyde concentration (P = 0.005 and 0.017, respectively). The decrease of sperm concentration was greater for Group 2 than for Group 1 (P = 0.031). We concluded that transient scrotal hyperthermia seriously, but reversibly, negatively affected the spermatogenesis, oxidative stress may be involved in this process. In addition, intermittent heat exposure more seriously suppresses the spermatogenesis compared to consecutive heat exposure. This may be indicative for clinical infertility etiology analysis and the design of contraceptive methods based on heat stress.
PMCID: PMC4492061  PMID: 25652627
hyperthermia; oxidative stress; seminal plasma biochemical markers; sperm parameters; spermatogenesis
7.  Pyranopterin Dithiolene Distortions Relevant to Electron Transfer in Xanthine Oxidase/Dehydrogenase 
Inorganic Chemistry  2014;53(14):7077-7079.
The reducing substrates 4-thiolumazine and 2,4-dithiolumazine have been used to form MoIV-product complexes with xanthine oxidase (XO) and xanthine dehydrogenase. These MoIV-product complexes display an intense metal-to-ligand charge-transfer (MLCT) band in the near-infrared region of the spectrum. Optical pumping into this MLCT band yields resonance Raman spectra of the Mo site that are devoid of contributions from the highly absorbing FAD and 2Fe2S clusters in the protein. The resonance Raman spectra reveal in-plane bending modes of the bound product and low-frequency molybdenum dithiolene and pyranopterin dithiolene vibrational modes. This work provides keen insight into the role of the pyranopterin dithiolene in electron-transfer reactivity.
The reducing substrates 4-thiolumazine and 2,4-dithiolumazine have been used to form MoIV-product complexes in xanthine oxidase (XO) and xanthine dehydrogenase (XDH). The MoIV-product complexes absorb in the near-infrared (NIR) region of the spectrum. Optical pumping into this NIR metal-to-ligand charge-transfer band reveals in-plane bending modes of the bound product in addition to low-frequency molybdenum dithiolene and pyranopterin dithiolene (pyranopterin ditholene) vibrational modes. The work provides insight into how pyranopterin ditholene is coupled to redox changes at the Mo site and how pyranopterin ditholene functions as an electron-transfer conduit in the oxidative half-reaction of XO/XDH.
PMCID: PMC4215880  PMID: 24979205
8.  KDM4B as a Target for Prostate Cancer: Structural Analysis and Selective Inhibition by a Novel Inhibitor 
Journal of Medicinal Chemistry  2014;57(14):5975-5985.
The KDM4/JMJD2 Jumonji C-containing histone lysine demethylases (KDM4A–KDM4D), which selectively remove the methyl group(s) from tri/dimethylated lysine 9/36 of H3, modulate transcriptional activation and genome stability. The overexpression of KDM4A/KDM4B in prostate cancer and their association with androgen receptor suggest that KDM4A/KDM4B are potential progression factors for prostate cancer. Here, we report the crystal structure of the KDM4B·pyridine 2,4-dicarboxylic acid·H3K9me3 ternary complex, revealing the core active-site region and a selective K9/K36 site. A selective KDM4A/KDM4B inhibitor, 4, that occupies three subsites in the binding pocket is identified by virtual screening. Pharmacological and genetic inhibition of KDM4A/KDM4B significantly blocks the viability of cultured prostate cancer cells, which is accompanied by increased H3K9me3 staining and transcriptional silencing of growth-related genes. Significantly, a substantial portion of differentially expressed genes are AR-responsive, consistent with the roles of KDM4s as critical AR activators. Our results point to KDM4 as a useful therapeutic target and identify a new inhibitor scaffold.
PMCID: PMC4216216  PMID: 24971742
9.  FctClus: A Fast Clustering Algorithm for Heterogeneous Information Networks 
PLoS ONE  2015;10(6):e0130086.
It is important to cluster heterogeneous information networks. A fast clustering algorithm based on an approximate commute time embedding for heterogeneous information networks with a star network schema is proposed in this paper by utilizing the sparsity of heterogeneous information networks. First, a heterogeneous information network is transformed into multiple compatible bipartite graphs from the compatible point of view. Second, the approximate commute time embedding of each bipartite graph is computed using random mapping and a linear time solver. All of the indicator subsets in each embedding simultaneously determine the target dataset. Finally, a general model is formulated by these indicator subsets, and a fast algorithm is derived by simultaneously clustering all of the indicator subsets using the sum of the weighted distances for all indicators for an identical target object. The proposed fast algorithm, FctClus, is shown to be efficient and generalizable and exhibits high clustering accuracy and fast computation speed based on a theoretic analysis and experimental verification.
PMCID: PMC4474961  PMID: 26090857
10.  Differences in Unfolded Protein Response Pathway Activation in the Lenses of Three Types of Cataracts 
PLoS ONE  2015;10(6):e0130705.
To investigate the activation of three unfolded protein response (UPR) pathways in the lenses of age-related, high myopia-related and congenital cataracts.
Methods and Materials
Lens specimens were collected from patients during small incision cataract surgery. Lenses from young cadaver eyes were collected as normal controls. Real-time PCR and Western blotting were performed to detect the expression of GRP78, p-eIF2α, spliced XBP1, ATF6, ATF4 and p-IRE1α in the lenses of normal human subjects and patients with age-related, myopia-related or congenital cataracts.
In the lenses of the age-related and high myopia-related cataract groups, the protein levels of ATF6, p-eIF2α and p-IRE1α and the gene expression levels of spliced XBP1, GRP78, ATF6 and ATF4 were greatly increased. Additionally, in the congenital cataract group, the protein levels of p-eIF2α and p-IRE1α and the gene expression levels of spliced XBP1, GRP78 and ATF4 were greatly increased. However, the protein and gene expression levels of ATF6 were not up-regulated in the congenital cataract group compared with the normal control group.
The UPR is activated via different pathways in the lenses of age-related, high myopia-related and congenital cataracts. UPR activation via distinct pathways might play important roles in cataractogenesis mechanisms in different types of cataracts.
PMCID: PMC4475046  PMID: 26091066
11.  Mining and identification of polyunsaturated fatty acid synthesis genes active during camelina seed development using 454 pyrosequencing 
BMC Plant Biology  2015;15:147.
Camelina (Camelina sativa L.) is well known for its high unsaturated fatty acid content and great resistance to environmental stress. However, little is known about the molecular mechanisms of unsaturated fatty acid biosynthesis in this annual oilseed crop. To gain greater insight into this mechanism, the transcriptome profiles of seeds at different developmental stages were analyzed by 454 pyrosequencing.
Sequencing of two normalized 454 libraries produced 831,632 clean reads. A total of 32,759 unigenes with an average length of 642 bp were obtained by de novo assembly, and 12,476 up-regulated and 12,390 down-regulated unigenes were identified in the 20 DAF (days after flowering) library compared with the 10 DAF library. Functional annotations showed that 220 genes annotated as fatty acid biosynthesis genes were up-regulated in 20 DAF sample. Among them, 47 candidate unigenes were characterized as responsible for polyunsaturated fatty acid synthesis. To verify unigene expression levels calculated from the transcriptome analysis results, quantitative real-time PCR was performed on 11 randomly selected genes from the 220 up-regulated genes; 10 showed consistency between qRT-PCR and 454 pyrosequencing results.
Investigation of gene expression levels revealed 32,759 genes involved in seed development, many of which showed significant changes in the 20 DAF sample compared with the 10 DAF sample. Our 454 pyrosequencing data for the camelina transcriptome provide an insight into the molecular mechanisms and regulatory pathways of polyunsaturated fatty acid biosynthesis in camelina. The genes characterized in our research will provide candidate genes for the genetic modification of crops.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0513-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4470060  PMID: 26084534
Camelina sativa; Oil crop; Polyunsaturated fatty acid; Transcriptome; Gene expression; qRT-PCR
12.  HCG-Activated Human Peripheral Blood Mononuclear Cells (PBMC) Promote Trophoblast Cell Invasion 
PLoS ONE  2015;10(6):e0125589.
Successful embryo implantation and placentation depend on appropriate trophoblast invasion into the maternal endometrial stroma. Human chorionic gonadotropin (hCG) is one of the earliest embryo-derived secreted signals in the peripheral blood mononuclear cells (PBMC) that abundantly expresses hCG receptors. The aims of this study were to estimate the effect of human embryo–secreted hCG on PBMC function and investigate the role and underlying mechanisms of activated PBMC in trophoblast invasion. Blood samples were collected from women undergoing benign gynecological surgery during the mid-secretory phase. PBMC were isolated and stimulated with or without hCG for 0 or 24 h. Interleukin-1β (IL-1β) and leukemia inhibitory factor (LIF) expressions in PBMC were detected by enzyme-linked immunosorbent assay and real-time polymerase chain reaction (PCR). The JAR cell line served as a model for trophoblast cells and was divided into four groups: control, hCG only, PBMC only, and PBMC with hCG. JAR cell invasive and proliferative abilities were detected by trans-well and CCK8 assays and matrix metalloproteinase (MMP)-2 (MMP-2), MMP-9, vascular endothelial growth factor (VEGF), tissue inhibitor of metalloproteinase (TIMP)-1, and TIMP-2 expressions in JAR cells were detected by western blotting and real-time PCR analysis. We found that hCG can remarkably promote IL-1β and LIF promotion in PBMC after 24-h culture. PBMC activated by hCG significantly increased the number of invasive JAR cells in an invasion assay without affecting proliferation, and hCG-activated PBMC significantly increased MMP-2, MMP-9, and VEGF and decreased TIMP-1 and TIMP-2 expressions in JAR cells in a dose-dependent manner. This study demonstrated that hCG stimulates cytokine secretion in human PBMC and could stimulate trophoblast invasion.
PMCID: PMC4472760  PMID: 26087261
13.  Synthesis, Biological, and Biophysical Studies of DAG-indololactones Designed as Selective Activators of RasGRP 
Bioorganic & medicinal chemistry  2014;22(12):3123-3140.
The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain-containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma, suggesting that the discovery of selective ligands could have potential therapeutic value. Thus far, the N-methyl-substituted indololactone 1 is the agonist with the highest reported potency and selectivity for RasGRP relative to PKC. Here we present the synthesis, binding studies, cellular assays and biophysical analysis of interactions with model membranes of a family of regioisomers of 1 (compounds 2 to 5) that differ in the position of the linkage between the indole ring and the lactone moiety. These structural variations were studied to explore the interaction of the active complex (C1 domain-ligand) with cellular membranes, which is believed to be an important factor for selectivity in the activation of DAG-responsive C1 domain containing signaling proteins. All compounds were potent and selective activators of RasGRP when compared to PKCα with selectivities ranging from 6 to 65 fold. However, the parent compound 1 was appreciably more selective than any of the other isomers. In intact cells, modest differences in the patterns of translocation of the C1 domain targets were observed. Biophysical studies using giant vesicles as model membranes did show substantial differences in terms of molecular interactions impacting lipid organization, dynamics and membrane insertion. However, these differences did not yield correspondingly large changes in patterns of biological response, at least for the parameters examined.
PMCID: PMC4104769  PMID: 24794745
Indolo-lactones; C1 domain; RasGRP; cancer
14.  Detection of superficial esophageal squamous cell neoplasia by chromoendoscopy-guided confocal laser endomicroscopy 
AIM: To evaluate the diagnostic potential of Lugol’s chromoendoscopy-guided confocal laser endomicroscopy (CLE) in detecting superficial esophageal squamous cell neoplasia (ESCN).
METHODS: Between December 2008 and September 2010, a total of 52 patients were enrolled at the Chinese PLA General Hospital in Beijing, China. First, Lugol’s chromoendoscopy-guided CLE was performed in these patients and the CLE in vivo histological diagnosis was recorded. Then, chromoendoscopy-guided biopsy was performed in the same patients by another endoscopist who was blinded to the CLE findings. Based on the biopsy and CLE diagnosis, en bloc endoscopic resection was performed. The CLE in vivo diagnosis and the histological diagnosis of biopsy of ESCN were compared, using a histological examination of the endoscopic resection specimens as the standard reference.
RESULTS: A total of 152 chromoendoscopy-guided biopsies were obtained from 56 lesions. In the 56 lesions of 52 patients, a total of 679 CLE images were obtained vs 152 corresponding biopsies. The sensitivity, specificity, negative predictive value and positive predictive value of chromoendoscopy-guided CLE compared with biopsy were 95.7% vs 82% (P < 0.05), 90% vs 70% (P < 0.05), 81.8% vs 46.7% (P < 0.05), and 97.8% vs 92.7% (P > 0.05), respectively. There was a significant improvement in sensitivity, specificity, negative predictive value, and accuracy when comparing chromoendoscopy-guided CLE with biopsy.
CONCLUSION: Lugol’s chromoendoscopy-guided CLE is a real-time, non-invasive endoscopic diagnostic technology; the accuracy of the detection of superficial ESCN is equivalent to or may be superior to biopsy histology.
PMCID: PMC4462739  PMID: 26078575
Superficial esophageal neoplasia; Squamous cell neoplasm; Confocal endomicroscopy; Endoscopic submucosal dissection; Chromoendoscopy
15.  Decreased Resting-State Interhemispheric Functional Connectivity in Parkinson's Disease 
BioMed Research International  2015;2015:692684.
Background. Abnormalities in white matter integrity and specific functional network alterations have been increasingly reported in patients with Parkinson's disease (PD). However, little is known about the inter-hemispheric interaction in PD. Methods. Fifty-one drug naive patients with PD and 51 age- and gender-matched healthy subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI) scans. We compared the inter-hemispheric resting-state functional connectivity between patients with PD and healthy controls, using the voxel-mirrored homotopic connectivity (VMHC) approach. Then, we correlated the results from VMHC and clinical features in PD patients. Results. Relative to healthy subject, patients exhibited significantly lower VMHC in putamen and cortical regions associated with sensory processing and motor control (involving sensorimotor and supramarginal cortex), which have been verified to play a critical role in PD. In addition, there were inverse relationships between the UPDRS motor scores and VMHC in the sensorimotor, and between the illness duration and VMHC in the supramarginal gyrus in PD patients. Conclusions. Our results suggest that the functional coordination between homotopic brain regions is impaired in PD patients, extending previous notions about the disconnection of corticostriatal circuit by providing new evidence supporting a disturbance in inter-hemispheric connections in PD.
PMCID: PMC4477209  PMID: 26180807
16.  Molecular architecture and mechanism of the anaphase-promoting complex 
Nature  2014;513(7518):388-393.
The ubiquitination of cell cycle regulatory proteins by the anaphase-promoting complex/cyclosome (APC/C) controls sister chromatid segregation, cytokinesis and the establishment of G1. The APC/C is an unusually large multimeric cullin-RING ligase. Its activity is strictly dependent on regulatory coactivator subunits that promote APC/C – substrate interactions and stimulate its catalytic reaction. Because the structures of many APC/C subunits and their organization within the assembly are unknown, the molecular basis for these processes is poorly understood. Here, from a cryo-EM reconstruction of a human APC/C-coactivator-substrate complex at 7.4 Å resolution, we have determined the complete secondary structural architecture of the complex. With this information we identified protein folds for structurally uncharacterized subunits, and the definitive location of all 20 APC/C subunits within the 1.2 MDa assembly. Comparison with apo APC/C shows that coactivator promotes a profound allosteric transition involving displacement of the cullin-RING catalytic subunits relative to the degron recognition module of coactivator and Apc10. This transition is accompanied by increased flexibility of the cullin-RING subunits and enhanced affinity for UbcH10~ubiquitin, changes which may contribute to coactivator-mediated stimulation of APC/C E3 ligase activity.
PMCID: PMC4456660  PMID: 25043029
17.  The Use of Chemical-Chemical Interaction and Chemical Structure to Identify New Candidate Chemicals Related to Lung Cancer 
PLoS ONE  2015;10(6):e0128696.
Lung cancer causes over one million deaths every year worldwide. However, prevention and treatment methods for this serious disease are limited. The identification of new chemicals related to lung cancer may aid in disease prevention and the design of more effective treatments. This study employed a weighted network, constructed using chemical-chemical interaction information, to identify new chemicals related to two types of lung cancer: non-small lung cancer and small-cell lung cancer. Then, a randomization test as well as chemical-chemical interaction and chemical structure information were utilized to make further selections. A final analysis of these new chemicals in the context of the current literature indicates that several chemicals are strongly linked to lung cancer.
PMCID: PMC4457841  PMID: 26047514
18.  The Prevalence and Associated Risk Factors of Impaired Glucose Regulation in Chinese Adults: A Population-Based Cross-Sectional Study 
The goal of this study was to determine the prevalence and associated risk factors of impaired glucose regulation (IGR) in the population of Tongzhou, China, and to provide scientific basis for preventive interventions. In the study, the overall age-standardized prevalence of IGR (16.0%) in Tongzhou residents was higher than that in the national population (15.0%). There was no significant geographic difference in prevalence of IGR between urban and rural males. Older age, elevated blood pressure, high serum lipids, overweight, and central obesity were significantly associated with increased risk of IGR.
PMCID: PMC4468349  PMID: 26136780
19.  Structures and mechanism for the design of highly potent glucocorticoids 
Cell Research  2014;24(6):713-726.
The evolution of glucocorticoid drugs was driven by the demand of lowering the unwanted side effects, while keeping the beneficial anti-inflammatory effects. Potency is an important aspect of this evolution as many undesirable side effects are associated with use of high-dose glucocorticoids. The side effects can be minimized by highly potent glucocorticoids that achieve the same treatment effects at lower doses. This demand propelled the continuous development of synthetic glucocorticoids with increased potencies, but the structural basis of their potencies is poorly understood. To determine the mechanisms underlying potency, we solved the X-ray structures of the glucocorticoid receptor (GR) ligand-binding domain (LBD) bound to its endogenous ligand, cortisol, which has relatively low potency, and a highly potent synthetic glucocorticoid, mometasone furoate (MF). The cortisol-bound GR LBD revealed that the flexibility of the C1-C2 single bond in the steroid A ring is primarily responsible for the low affinity of cortisol to GR. In contrast, we demonstrate that the very high potency of MF is achieved by its C-17α furoate group completely filling the ligand-binding pocket, thus providing additional anchor contacts for high-affinity binding. A single amino acid in the ligand-binding pocket, Q642, plays a discriminating role in ligand potency between MF and cortisol. Structure-based design led to synthesis of several novel glucocorticoids with much improved potency and efficacy. Together, these results reveal key structural mechanisms of glucocorticoid potency and provide a rational basis for developing novel highly potent glucocorticoids.
PMCID: PMC4042175  PMID: 24763108
glucocorticoids; glucocorticoid receptor; potency; cortisol; mometasone furoate
20.  Regulation of nuclear–cytoplasmic shuttling and function of Family with sequence similarity 13, member A (Fam13a), by B56-containing PP2As and Akt 
Molecular Biology of the Cell  2015;26(6):1160-1173.
FAM13A is a novel human lung disease–associated gene. Fam13a is dispensable but is capable of inducing Wnt signaling. Nuclear localization of Fam13a is important for its function in the Wnt pathway. Akt/PP2A-dependent reversible phosphorylation on Ser-322 is a molecular switch that controls nuclear–cytoplasmic shuttling of Fam13a.
Recent genome-wide association studies reveal that the FAM13A gene is associated with human lung function and a variety of lung diseases, including chronic obstructive pulmonary disease, asthma, lung cancer, and pulmonary fibrosis. The biological functions of Fam13a, however, have not been studied. In an effort to identify novel substrates of B56-containing PP2As, we found that B56-containing PP2As and Akt act antagonistically to control reversible phosphorylation of Fam13a on Ser-322. We show that Ser-322 phosphorylation acts as a molecular switch to control the subcellular distribution of Fam13a. Fam13a shuttles between the nucleus and cytoplasm. When Ser-322 is phosphorylated by Akt, the binding between Fam13a and 14-3-3 is enhanced, leading to cytoplasmic sequestration of Fam13a. B56-containing PP2As dephosphorylate phospho–Ser-322 and promote nuclear localization of Fam13a. We generated Fam13a-knockout mice. Fam13a-mutant mice are viable and healthy, indicating that Fam13a is dispensable for embryonic development and physiological functions in adult animals. Intriguingly, Fam13a has the ability to activate the Wnt pathway. Although Wnt signaling remains largely normal in Fam13a-knockout lungs, depletion of Fam13a in human lung cancer cells causes an obvious reduction in Wnt signaling activity. Our work provides important clues to elucidating the mechanism by which Fam13a may contribute to human lung diseases.
PMCID: PMC4357514  PMID: 25609086
21.  Tumor cell p38 MAPK: A trigger of cancer bone osteolysis 
Osteolytic bone destruction is a hallmark of bone-metastatic cancers. Current therapy is unable to completely cure or prevent this disease in patients. The p38 mitogen-activated protein kinase (MAPK) affects a diverse range of intracellular responses with well-known roles in development, cell-cycle and differentiation, inflammation, apoptosis, senescence, and tumorigenesis. This article is an overview of the contribution of tumor cell-expressed p38 MAPK to the regulation of osteoclastogenesis, osteoblastogenesis, and osteolyticbone lesions.
PMCID: PMC4448135  PMID: 26029733
p38 MAPK; bone destruction; multiple myeloma; breast cancer; cytokines
22.  The role of perioperative oral nutritional supplementation in elderly patients after hip surgery 
The effect of perioperative oral nutritional supplementation (ONS) on elderly patients after hip surgery remains controversial. This study intended to ascertain whether perioperative ONS is beneficial for the rehabilitation of elderly patients after hip surgery.
Materials and methods
We searched databases including PubMed, Embase, and the Cochrane Central Register of Controlled Trials for articles published up to May 2014. Randomized controlled trials of ONS for elderly patients after hip surgery were included.
The combined trials showed that ONS had a positive effect on the serum total protein (P<0.00001) and led to a significantly decreased number of complications (P=0.0005). Furthermore, data from the infection subgroups showed significant decreases in wound infection (P=0.02), respiratory infection (P=0.04), and urinary tract infection (P=0.03). Clinical observation suggests that the intervention may improve the level of serum albumin, although the data did not reach statistical significance (P=0.48). Regarding mortality, there was no significant statistical difference between the intervention group and the control (P=0.93).
Based on the evidence available, this meta-analysis is consistent with the hypothesis that perioperative ONS can help elderly patients recover after hip surgery and reduce complications.
PMCID: PMC4433048  PMID: 26005339
oral nutrition; elderly patient; hip surgery; meta-analysis
23.  BMP7 and EREG Contribute to the Inductive Potential of Dental Mesenchyme 
Scientific Reports  2015;5:9903.
Odontogenesis is accomplished by reciprocal signaling between the epithelial and mesenchymal compartments. It is generally accepted that the inductive mesenchyme is capable of inducing the odontogenic commitment of both dental and non-dental epithelial cells. However, the duration of this signal in the developing dental mesenchyme and whether adult dental pulp tissue maintains its inductive capability remain unclear. This study investigated the contribution of growth factors to regulating the inductive potential of the dental mesenchyme. Human oral epithelial cells (OEs) were co-cultured with either human dental mesenchymal/papilla cells (FDPCs) or human dental pulp cells (ADPCs) under 2-dimensional or 3-dimensional conditions. Odontogenic-associated genes and proteins were detected by qPCR and immunofluorescence, respectively, and significant differences were observed between the two co-culture systems. The BMP7 and EREG expression levels in FDPCs were significantly higher than in ADPCs, as indicated by human growth factor PCR arrays and immunofluorescence analyses. OEs co-cultured with ADPCs supplemented with BMP7 and EREG expressed ameloblastic differentiation genes. Our study suggests that BMP7 and EREG expression in late bell-stage human dental papilla contributes to the inductive potential of dental mesenchyme. Furthermore, adult dental pulp cells supplemented with these two growth factors re-established the inductive potential of postnatal dental pulp tissue.
PMCID: PMC4424660  PMID: 25952286
24.  Tetraspanin Family Member, CD82, Regulates Expression of EZH2 via Inactivation of p38 MAPK Signaling in Leukemia Cells 
PLoS ONE  2015;10(5):e0125017.
We recently found that the tetraspanin family member, CD82, which is aberrantly expressed in chemotherapy-resistant CD34+/CD38− acute myelogenous leukemia (AML) cells, negatively regulates matrix metalloproteinase 9, and plays an important role in enabling CD34+/CD38− AML cells to adhere to the bone marrow microenvironment. This study explored novel functions of CD82 that contribute to AML progression.
Materials and Methods
We employed microarray analysis comparing the gene expression profiles between CD34+/CD38− AML cells transduced with CD82 shRNA and CD34+/CD38− AML cells transduced with control shRNA. Real-time RT-PCR and western blot analysis were performed to examine the effect of CD82 knockdown on the expression of the polycomb group member, enhancer of zeste homolog 2 (EZH2), in leukemia cells. A chromatin immunoprecipitation assay was performed to examine the effect of CD82 expression on the amount of EZH2 bound to the promoter regions of tumor suppressor genes in leukemia cells. We also utilized methylation-specific PCR to examine whether CD82 expression influences the methylation status of the tumor suppressor gene promoter regions in leukemia cells.
Microarray analysis revealed that levels of EZH2 decreased after shRNA-mediated depletion of CD82 in CD34+/CD38− AML cells. Moreover, the antibody-mediated blockade of CD82 in leukemia cells lowered EZH2 expression via activation of p38 MAPK signaling, decreased the amount of EZH2 bound to the promoter regions of the tumor suppressor genes, and inhibited histone H3 lysine 27 trimethylation in these promoter regions, resulting in upregulation of the tumor suppressors at both the mRNA and protein levels.
PMCID: PMC4425466  PMID: 25955299
25.  HIV Protease Inhibitors Sensitize Human Head and Neck Squamous Carcinoma Cells to Radiation by Activating Endoplasmic Reticulum Stress 
PLoS ONE  2015;10(5):e0125928.
Human head and neck squamous cell carcinoma (HNSCC) is the sixth most malignant cancer worldwide. Despite significant advances in the delivery of treatment and surgical reconstruction, there is no significant improvement of mortality rates for this disease in the past decades. Radiotherapy is the core component of the clinical combinational therapies for HNSCC. However, the tumor cells have a tendency to develop radiation resistance, which is a major barrier to effective treatment. HIV protease inhibitors (HIV PIs) have been reported with radiosensitizing activities in HNSCC cells, but the underlying cellular/molecular mechanisms remain unclear. Our previous study has shown that HIV PIs induce cell apoptosis via activation of endoplasmic reticulum (ER) stress. The aim of this study was to examine the role of ER stress in HIV PI-induced radiosensitivity in human HNSCC.
Methodology and Principal Findings
HNSCC cell lines, SQ20B and FaDu, and the most commonly used HIV PIs, lopinavir and ritonavir (L/R), were used in this study. Clonogenic assay was used to assess the radiosensitivity. Cell viability, apoptosis and cell cycle were analyzed using Cellometer Vision CBA. The mRNA and protein levels of ER stress-related genes (eIF2α, CHOP, ATF-4, and XBP-1), as well as cell cycle related protein, cyclin D1, were detected by real time RT-PCR and Western blot analysis, respectively. The results demonstrated that L/R dose-dependently sensitized HNSCC cells to irradiation and inhibited cell growth. L/R-induced activation of ER stress was correlated to down-regulation of cyclin D1 expression and cell cycle arrest under G0/G1 phase.
Conclusion and Significance
HIV PIs sensitize HNSCC cells to radiotherapy by activation of ER stress and induction of cell cycle arrest. Our results provided evidence that HIV PIs can be potentially used in combination with radiation in the treatment of HNSCC.
PMCID: PMC4416809  PMID: 25933118

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