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1.  Glucose variability for cardiovascular risk factors in type 2 diabetes: a meta-analysis 
It is consensus that glucose variability (GV) plays an important role in maccomplications of type 2 diabetes, but whether GV has a causal role is not yet clear for cardiovascular disease (CVD). This study sought to explore the effect on GV for CVD risk factors with type 2 diabetes.
The systematic literature search was performed to identify all GV and CVD risk factors, including total cholesterol (TC), LDL cholesterol (LDL-C), triglyceride (TG), HDL cholesterol (HDL-C), Body Mass Index (BMI), waist circumference (WC), High-Sensitivity C-reactive protein (Hs-CRP), Homeostasis model assessment (HOMA) and carotid intima-media thickness (IMT). Preferred Reporting Items was synthesized for Systematic reviews and Meta Analyses guideline. And the pooled analyses were undertaken using Review Manager 5.3.
Twenty two studies were included with a total of 1143 patients in high glucose variability group (HGVG) and 1275 patients low glucose variability group (LGVG). Among these selected CVD risk factors, HOMA-IR and reduced IMT were affected by GV. HOMA-IR level was significantly lower in LGVG than in HGVG (MD = 0.58, 95% CI: 0.26 to 0.91, P = 0.0004), with evidence of heterogeneity between studies (I2 = 0%; P = 0.47).
Reduced IMT level was significantly lower in LGVG than in HGVG (SMD = 0.28, 95% CI: 0.09 to 0.47, P = 0.003), with evidence of heterogeneity between studies (I2 = 0%; P = 0.48). However, the others were no significant statistical difference.
Among these selected CVD risk factors in type 2 diabetes, minimizing GV could improve insulin resistance and reduced IMT, consistent with a lowering in risk of CVD.
Electronic supplementary material
The online version of this article (10.1186/s40200-017-0323-5) contains supplementary material, which is available to authorized users.
PMCID: PMC5686902
2.  Identification of a gene signature associated with radiotherapy and prognosis in gliomas 
Oncotarget  2017;8(51):88974-88987.
Glioma is one of the most common primary brain tumors with poor prognosis. Although radiotherapy is an important treatment method for gliomas, the efficacy is still limited by the high occurrence of radioresistance and the underlying molecular mechanism is unclear. Here, we performed a data mining work based on four glioma expression datasets. These datasets were classified into training set and validation set. Radiotherapy-induced differential expressed genes and prognosis-associated genes were screened using different classifiers. The Kaplan-Meier curves along with the two-sided Log Rank (Mantel-Cox) test were used to evaluate overall survival. We found the gene expression profiles of gliomas between those patients received radiotherapy and those patients without received radiotherapy were quite different. A 20-gene signature was identified, which was associated with radiotherapy.Furthermore, a novel 5-gene signature (HOXC10, LOC101928747, CYB561D2, RPL36A and RPS4XP2) as an independent predictor of glioma patients’ prognosis was further derived from the 20-gene signature. These findings provided a new insight into the molecular mechanism of radioresistance in gliomas. The 5-gene signature might represent therapeutic target for gliomas.
PMCID: PMC5687662
glioma; prognosis; gene signature
3.  On the implication of structural zeros as independent variables in regression analysis: applications to alcohol research 
Journal of data science : JDS  2014;12(3):439-460.
In alcohol studies, drinking outcomes such as number of days of any alcohol drinking (DAD) over a period of time do not precisely capture the differences among subjects in a study population of interest. For example, the value of 0 on DAD could mean that the subject was continually abstinent from drinking such as lifetime abstainers or the subject was alcoholic, but happened not to use any alcohol during the period of interest. In statistics, zeros of the first kind are called structural zeros, to distinguish them from the sampling zeros of the second type. As the example indicates, the structural and sampling zeros represent two groups of subjects with quite different psychosocial outcomes. In the literature on alcohol use, although many recent studies have begun to explicitly account for the differences between the two types of zeros in modeling drinking variables as a response, none has acknowledged the implications of the different types of zeros when such modeling drinking variables are used as a predictor. This paper serves as the first attempt to tackle the latter issue and illustrate the importance of disentangling the structural and sampling zeros by using simulated as well as real study data.
PMCID: PMC5628625
number of days of drinking alcohol; NHANES; structural zero; zero-inflated count data; zero-inflated models for count data
4.  Culture conditions tailored to the cell of origin are critical for maintaining native properties and tumorigenicity of glioma cells 
Neuro-Oncology  2016;18(10):1413-1424.
Cell culture plays a pivotal role in cancer research. However, culture-induced changes in biological properties of tumor cells profoundly affect research reproducibility and translational potential. Establishing culture conditions tailored to the cancer cell of origin could resolve this problem. For glioma research, it has been previously shown that replacing serum with defined growth factors for neural stem cells (NSCs) greatly improved the retention of gene expression profile and tumorigenicity. However, among all molecular subtypes of glioma, our laboratory and others have previously shown that the oligodendrocyte precursor cell (OPC) rather than the NSC serves as the cell of origin for the proneural subtype, raising questions regarding the suitability of NSC-tailored media for culturing proneural glioma cells.
OPC-originated mouse glioma cells were cultured in conditions for normal OPCs or NSCs, respectively, for multiple passages. Gene expression profiles, morphologies, tumorigenicity, and drug responsiveness of cultured cells were examined in comparison with freshly isolated tumor cells.
OPC media-cultured glioma cells maintained tumorigenicity, gene expression profiles, and morphologies similar to freshly isolated tumor cells. In contrast, NSC-media cultured glioma cells gradually lost their OPC features and most tumor-initiating ability and acquired heightened sensitivity to temozolomide.
To improve experimental reproducibility and translational potential of glioma research, it is important to identify the cell of origin, and subsequently apply this knowledge to establish culture conditions that allow the retention of native properties of tumor cells.
PMCID: PMC5035523  PMID: 27106408
cell culture; glioma; oligodendrocyte precursor cell (OPC); neural stem cell (NSC); research reproducibility
5.  Gut Microbiome Associates With Lifetime Cardiovascular Disease Risk Profile Among Bogalusa Heart Study Participants 
Circulation research  2016;119(8):956-964.
Few studies have systematically assessed the influence of gut microbiota on cardiovascular disease (CVD) risk.
To examine the association between gut microbiota and lifetime CVD risk profile among 55 Bogalusa Heart Study (BHS) participants with the highest and 57 with the lowest lifetime burdens of CVD risk factors.
Methods and Results
16S rRNA sequencing was conducted on microbial DNA extracted from stool samples of the BHS participants. Alpha diversity, including measures of richness and evenness, and individual genera were tested for associations with lifetime CVD risk profile. Multivariable regression techniques were employed to adjust for age, gender, and race (Model 1), along with body mass index (BMI) (Model 2) and both BMI and diet (Model 3). In Model 1, odds ratios (95% confidence intervals) for each standard deviation increase in richness, measured by the number of observed operational taxonomic units, Chao 1 index, and abundance-based coverage estimator, were 0.62 (0.39, 0.99), 0.61 (0.38, 0.98), and 0.63 (0.39, 0.99), respectively. Associations were consistent in Models 2 and 3. Four genera were enriched among those with high versus low CVD risk profile in all models. Model 1 p-values were: 2.12×10−3, 7.95×10−5, 4.39×10−4, and 1.51×10−4 for Prevotella 2, Prevotella 7, Tyzzerella and Tyzzerella 4, respectively. Two genera were depleted among those with high versus low CVD risk profile in all models. Model 1 P-values were: 2.96×10−6 and 1.82×10−4 for Alloprevotella and Catenibacterium, respectively.
The current study identified associations of overall microbial richness and six microbial genera with lifetime CVD risk.
PMCID: PMC5045790  PMID: 27507222
Microbiota; cardiovascular disease risk factors; lipids; blood pressure; blood glucose; Risk Factors; Cardiovascular Disease; Epidemiology; Genetics
6.  Analysis of chromatin accessibility in human epidermis identifies putative barrier dysfunction-sensing enhancers 
PLoS ONE  2017;12(9):e0184500.
To identify putative gene regulatory regions that respond to epidermal injury, we mapped chromatin dynamics in a stratified human epidermis during barrier maturation and disruption. Engineered skin substitutes (ESS) cultured at the air-liquid interface were used as a model of developing human epidermis with incomplete barrier formation. The epidermal barrier stabilized following engraftment onto immunocompromised mice, and was compromised again upon injury. Modified formaldehyde-assisted isolation of regulatory elements (FAIRE) was used to identify accessible genomic regions characteristic of monolayer keratinocytes, ESS in vitro, grafted ESS, and tape-stripped ESS graft. We mapped differentiation- and maturation-associated changes in transcription factor binding sites enriched at each stage and observed overrepresentation of AP-1 gene family motifs in barrier-deficient samples. Transcription of TSLP, an important effector of immunological memory in response to allergen exposure, was dramatically elevated in our barrier-deficient samples. We identified dynamic DNA elements that correlated with TSLP induction and may contain enhancers that regulate TSLP. Two dynamic regions were located near the TSLP promoter and overlapped with allergy-associated SNPs rs17551370 and rs2289877, strongly implicating these loci in the regulation of TSLP expression in allergic disease. Additional dynamic chromatin regions ~250kb upstream of the TSLP promoter were found to be in high linkage disequilibrium with allergic disease SNPs. Taken together, these results define dynamic chromatin accessibility changes during epidermal development and dysfunction.
PMCID: PMC5617145  PMID: 28953906
7.  BMP4/LIF or RA/Forskolin Suppresses the Proliferation of Neural Stem Cells Derived from Adult Monkey Brain 
Stem Cells International  2017;2017:7012405.
Monkeys are much closer to human and are the most common nonhuman primates which are used in biomedical studies. Neural progenitor cells can originate from the hippocampus of adult monkeys. Despite a few reports, the detailed properties of monkey neural stem cells (NSCs) and their responses to cytokine are still unclear. Here, we derive NSCs from an adult monkey brain and demonstrate that BMP4 inhibits cell proliferation and affects cell morphology of monkey NSCs. Combined treatment of BMP4 and LIF or RA and Forskolin represses the proliferation of monkey NSCs. We also show that BMP4 may promote monkey NSC quiescence. Our study therefore provides implications for NSC-based cell therapy of brain injury in the future.
PMCID: PMC5632485
8.  Efficient and Fast Differentiation of Human Neural Stem Cells from Human Embryonic Stem Cells for Cell Therapy 
Stem Cells International  2017;2017:9405204.
Stem cell-based therapies have been used for repairing damaged brain tissue and helping functional recovery after brain injury. Aberrance neurogenesis is related with brain injury, and multipotential neural stem cells from human embryonic stem (hES) cells provide a great promise for cell replacement therapies. Optimized protocols for neural differentiation are necessary to produce functional human neural stem cells (hNSCs) for cell therapy. However, the qualified procedure is scarce and detailed features of hNSCs originated from hES cells are still unclear. In this study, we developed a method to obtain hNSCs from hES cells, by which we could harvest abundant hNSCs in a relatively short time. Then, we examined the expression of pluripotent and multipotent marker genes through immunostaining and confirmed differentiation potential of the differentiated hNSCs. Furthermore, we analyzed the mitotic activity of these hNSCs. In this report, we provided comprehensive features of hNSCs and delivered the knowledge about how to obtain more high-quality hNSCs from hES cells which may help to accelerate the NSC-based therapies in brain injury treatment.
PMCID: PMC5624175
9.  Epithelial heparan sulfate regulates Sonic Hedgehog signaling in lung development 
PLoS Genetics  2017;13(8):e1006992.
The tree-like structure of the mammalian lung is generated from branching morphogenesis, a reiterative process that is precisely regulated by numerous factors. How the cell surface and extra cellular matrix (ECM) molecules regulate this process is still poorly understood. Herein, we show that epithelial deletion of Heparan Sulfate (HS) synthetase Ext1 resulted in expanded branching tips and reduced branching number, associated with several mesenchymal developmental defects. We further demonstrate an expanded Fgf10 expression and increased FGF signaling activity in Ext1 mutant lungs, suggesting a cell non-autonomous mechanism. Consistent with this, we observed reduced levels of SHH signaling which is responsible for suppressing Fgf10 expression. Moreover, reactivating SHH signaling in mutant lungs rescued the tip dilation phenotype and attenuated FGF signaling. Importantly, the reduced SHH signaling activity did not appear to be caused by decreased Shh expression or protein stability; instead, biologically active form of SHH proteins were reduced in both the Ext1 mutant epithelium and surrounding wild type mesenchymal cells. Together, our study highlights the epithelial HS as a key player for dictating SHH signaling critical for lung morphogenesis.
Author summary
Defective development of the respiratory system leads to congenital or postnatal respiratory disorders. Although it is well established that lung morphogenesis is guided by interactions of multiple morphogen signaling pathways in epithelium and mesenchyme, how their regulatory functions are controlled by cell surface and extra cellular matrix (ECM) molecules is still largely unknown. Heparan Sulfate (HS) glycosaminoglycans are widely presented on the cell surface and in the extracellular matrix depending on the attached core proteins, and are thought to be important for transducing FGF signaling. The function of HS during lung development has not been studied in vivo. Here, using mouse genetics, we demonstrate that epithelial HS biosynthesis is critically required for lung branching morphogenesis. We reveal an unexpected role of epithelial HS in restricting FGF signaling. We show that depletion of epithelial HS leads to a dramatic loss of biologically active form of SHH, which is required for ensuring a proper expression of Fgf10. Our study demonstrates that the SHH-producing lung epithelial cells require HS to maintain the quality of the ligand at the source level and highlights epithelial HS as a critical regulator that dictates lung morphogenesis.
PMCID: PMC5597256  PMID: 28859094
10.  MiR-199a-3p suppresses proliferation and invasion of prostate cancer cells by targeting Smad1 
Oncotarget  2017;8(32):52465-52473.
This study was intended to analyze effects of miR-199a-3p and Smad1 on proliferation, migration and invasion of prostate cancer (PCa) cells.
MiR-199a-3p was significantly decreased in PCa tissues in comparison to that in adjacent normal tissues (P < 0.05). Over-expressed miR-199a-3p markedly suppressed proliferation and invasion of PCa cells (P < 0.05). MiR-199a-3p was negatively correlated with Smad1 expression, and overexpression of Smad1 could antagonize the effects of miR-199a-3p on PCa cells.
Materials and methods
The PCa tissues and their adjacent normal tissues were collected from 54 PCa patients. Expressions of miR-199a-3p and Smad1 mRNA in tissues and cells were evaluated with real-time quantitative polymerase chain reaction (RT-qPCR), and immunohistochemistry assay was used to detect Smad1 protein expressions. The target relationship between miR-199a-3p and Smad1 was assessed by luciferase reporter assay. The PCa cell lines (i.e. PC-3 cells) were transfected with miR-199a-3p mimics and Smad1-cDNA. MTT and Transwell assays were applied to detect proliferative, migratory and invasive abilities of PCa cells.
MiR-199a-3p suppressed proliferation and invasion of PCa cells by targeting Smad1.
PMCID: PMC5581043
MiR-199a-3p; Smad1; prostate cancer; proliferation; invasion
11.  Modulation of polypeptide conformation through donor–acceptor transformation of side-chain hydrogen bonding ligands 
Synthetic polypeptides have received increasing attention due to their ability to form higher ordered structures similar to proteins. The control over their secondary structures, which enables dynamic conformational changes, is primarily accomplished by tuning the side-chain hydrophobic or ionic interactions. Herein we report a strategy to modulate the conformation of polypeptides utilizing donor–acceptor interactions emanating from side-chain H-bonding ligands. Specifically, 1,2,3-triazole groups, when incorporated onto polypeptide side-chains, serve as both H-bond donors and acceptors at neutral pH and disrupt the α-helical conformation. When protonated, the resulting 1,2,3-triazolium ions lose the ability to act as H-bond acceptors, and the polypeptides regain their α-helical structure. The conformational change of triazole polypeptides in response to the donor-acceptor pattern was conclusively demonstrated using both experimental-based and simulation-based methods. We further showed the utility of this transition by designing smart, cell-penetrating polymers that undergo acid-activated endosomal escape in living cells.
Hydrogen bonding plays a major role in determining the tridimensional structure of biopolymers. Here, the authors show that control over a polypeptide conformation can be achieved by altering the donor-acceptor properties of side-chain triazole units via protonation-deprotonation.
PMCID: PMC5522480  PMID: 28733648
12.  Enrichment and verification of differentially expressed miRNAs in bursa of Fabricius in two breeds of duck 
The bursa of Fabricius (BF) is a central humoral immune organ belonging specifically to avians. Recent studies had suggested that miRNAs were active regulators involved in the immune processes. This study was to investigate the possible differences of the BF at miRNA level between two genetically disparate duck breeds.
Using Illumina next-generation sequencing, the miRNAs libraries of ducks were established.
The results showed that there were 66 differentially expressed miRNAs and 28 novel miRNAs in bursa. A set of abundant miRNAs (i.e., let-7, miR-146a-5p, miR-21-5p, miR-17~92) which are involved in immunity and disease were detected and the predicted target genes of the novel miRNAs were associated with duck high anti-adversity ability. By gene ontology analysis and enriching KEGG pathway, the targets of differential expressed miRNAs were mainly involved in immunity and disease, supporting that there were differences in the BF immune functions between the two duck breeds. In addition, the metabolic pathway had the maximum enriched target genes and some enriched pathways that were related to cell cycle, protein synthesis, cell proliferation and apoptosis. It indicted that the difference of metabolism may be one of the reasons leading the immune difference between the BF of two duck breeds.
This data lists the main differences in the BF at miRNAs level between two genetically disparate duck breeds and lays a foundation to carry out molecular assisted breeding of poultry in the future.
PMCID: PMC5495669  PMID: 27660025
Bursa of Fabricius; MiRNAs; Genetically Disparate Breeds; Gene Ontology; KEGG; Duck
13.  Disparities in infant hospitalizations in Indigenous and non-Indigenous populations in Quebec, Canada 
Infant mortality is higher in Indigenous than non-Indigenous populations, but comparable data on infant morbidity are lacking in Canada. We evaluated disparities in infant morbidities experienced by Indigenous populations in Canada.
We used linked population-based birth and health administrative data from Quebec, Canada, to compare hospitalization rates, an indicator of severe morbidity, in First Nations, Inuit and non-Indigenous singleton infants (< 1 year) born between 1996 and 2010.
Our cohort included 19 770 First Nations, 3930 Inuit and 225 380 non-Indigenous infants. Compared with non-Indigenous infants, all-cause hospitalization rates were higher in First Nations infants (unadjusted risk ratio [RR] 2.05, 95% confidence interval [CI] 1.99–2.11; fully adjusted RR 1.43, 95% CI 1.37–1.50) and in Inuit infants (unadjusted RR 1.96, 95% CI 1.87–2.05; fully adjusted RR 1.37, 95% CI 1.24–1.52). Higher risks of hospitalization (accounting for multiple comparisons) were observed for First Nations infants in 12 of 16 disease categories and for Inuit infants in 7 of 16 disease categories. Maternal characteristics (age, education, marital status, parity, rural residence and Northern residence) partly explained the risk elevations, but maternal chronic illnesses and gestational complications had negligible influence overall. Acute bronchiolitis (risk difference v. non-Indigenous infants, First Nations 37.0 per 1000, Inuit 39.6 per 1000) and pneumonia (risk difference v. non-Indigenous infants, First Nations 41.2 per 1000, Inuit 61.3 per 1000) were the 2 leading causes of excess hospitalizations in Indigenous infants.
First Nations and Inuit infants had substantially elevated burdens of hospitalizations as a result of diseases of multiple systems. The findings identify substantial unmet needs in disease prevention and medical care for Indigenous infants.
PMCID: PMC5449236  PMID: 28554947
14.  Rhinovirus infection results in stronger and more persistent genomic dysregulation: Evidence for altered innate immune response in asthmatics at baseline, early in infection, and during convalescence 
PLoS ONE  2017;12(5):e0178096.
Rhinovirus (HRV) is associated with the large majority of virus-induced asthma exacerbations in children and young adults, but the mechanisms remain poorly defined.
Asthmatics and non-asthmatic controls were inoculated with HRV-A16, and nasal epithelial samples were obtained 7 days before, 36 hours after, and 7 days after viral inoculation. RNA was extracted and subjected to RNA-seq analysis.
At baseline, 57 genes were differentially expressed between asthmatics and controls, and the asthmatics had decreased expression of viral replication inhibitors and increased expression of genes involved in inflammation. At 36 hours (before the emergence of peak symptoms), 1329 genes were significantly altered from baseline in the asthmatics compared to 62 genes in the controls. At this time point, asthmatics lacked an increase in IL-10 signaling observed in the controls. At 7 days following HRV inoculation, 222 genes were significantly dysregulated in the asthmatics, whereas only 4 genes were dysregulated among controls. At this time point, the controls but not asthmatics demonstrated upregulation of SPINK5.
As judged by the magnitude and persistence of dysregulated genes, asthmatics have a substantially different host response to HRV-A16 infection compared with non-asthmatic controls. Gene expression differences illuminate biologically plausible mechanisms that contribute to a better understanding of the pathogenesis of HRV-induced asthma exacerbations.
PMCID: PMC5446117  PMID: 28552993
15.  A Promising Approach to Integrally Evaluate the Disease Outcome of Cerebral Ischemic Rats Based on Multiple-Biomarker Crosstalk 
Disease Markers  2017;2017:9506527.
The study was designed to evaluate the disease outcome based on multiple biomarkers related to cerebral ischemia.
Rats were randomly divided into sham, permanent middle cerebral artery occlusion, and edaravone-treated groups. Cerebral ischemia was induced by permanent middle cerebral artery occlusion surgery in rats. To form a simplified crosstalk network, the related multiple biomarkers were chosen as S100β, HIF-1α, IL-1β, PGI2, TXA2, and GSH-Px. The levels or activities of these biomarkers in plasma were detected before and after ischemia. Concurrently, neurological deficit scores and cerebral infarct volumes were assessed. Based on a mathematic model, network balance maps and three integral disruption parameters (k, φ, and u) of the simplified crosstalk network were achieved.
The levels or activities of the related biomarkers and neurological deficit scores were significantly impacted by cerebral ischemia. The balance maps intuitively displayed the network disruption, and the integral disruption parameters quantitatively depicted the disruption state of the simplified network after cerebral ischemia. The integral disruption parameter u values correlated significantly with neurological deficit scores and infarct volumes.
Our results indicate that the approach based on crosstalk network may provide a new promising way to integrally evaluate the outcome of cerebral ischemia.
PMCID: PMC5463200
16.  Pattern analysis of schistosomiasis prevalence by exploring predictive modeling in Jiangling County, Hubei Province, P.R. China 
The prevalence of schistosomiasis remains a key public health issue in China. Jiangling County in Hubei Province is a typical lake and marshland endemic area. The pattern analysis of schistosomiasis prevalence in Jiangling County is of significant importance for promoting schistosomiasis surveillance and control in the similar endemic areas.
The dataset was constructed based on the annual schistosomiasis surveillance as well the socio-economic data in Jiangling County covering the years from 2009 to 2013. A village clustering method modified from the K-mean algorithm was used to identify different types of endemic villages. For these identified village clusters, a matrix-based predictive model was developed by means of exploring the one-step backward temporal correlation inference algorithm aiming to estimate the predicative correlations of schistosomiasis prevalence among different years. Field sampling of faeces from domestic animals, as an indicator of potential schistosomiasis prevalence, was carried out and the results were used to validate the results of proposed models and methods.
The prevalence of schistosomiasis in Jiangling County declined year by year. The total of 198 endemic villages in Jiangling County can be divided into four clusters with reference to the 5 years’ occurrences of schistosomiasis in human, cattle and snail populations. For each identified village cluster, a predictive matrix was generated to characterize the relationships of schistosomiasis prevalence with the historic infection level as well as their associated impact factors. Furthermore, the results of sampling faeces from the front field agreed with the results of the identified clusters of endemic villages.
The results of village clusters and the predictive matrix can be regard as the basis to conduct targeted measures for schistosomiasis surveillance and control. Furthermore, the proposed models and methods can be modified to investigate the schistosomiasis prevalence in other regions as well as be used for investigating other parasitic diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s40249-017-0303-5) contains supplementary material, which is available to authorized users.
PMCID: PMC5406921  PMID: 28446227
Schistosomiasis; Clustering; Predictive modelling
17.  Tissue expression profiles and transcriptional regulation of elongase of very long chain fatty acid 6 in bovine mammary epithelial cells 
PLoS ONE  2017;12(4):e0175777.
In mammals, very long chain fatty acids (VLCFAs) perform pleiotropic roles in a wide range of biological processes, such as cell membrane formation, cell signal transduction, and endocrine regulation. Beef and milk are abundant of palmitic acid which can be further elongated into stearic acid for synthesizing VLCFAs. Elongase of very long chain fatty acid 6 (ELOVL6) is a rate-limiting enzyme for converting palmitic acid to stearic acid. Consequently, investigating the tissue expression patterns and transcriptional regulation of bovine ELOVL6 can provide new insights into improving the composition of beneficial fats in cattle and expanding the knowledge of transcriptional regulation mechanism among domestic animals. In the current study, we found that bovine ELOVL6 expressed ubiquitously. Dual-luciferase reporter assay identified that the core promoter region (-130/-41 bp) was located in the second CpG island. In addition, the deletion mutation of binding sites demonstrated that sterol regulatory element binding transcription factor 1 (SREBF1) and specific protein 1 (SP1) both were able to stimulate bovine ELOVL6 promoter activity independently, while resulting the similar effect. To confirm these findings, further RNA interference assays were executed in bovine mammary epithelial cells (BMECs). In summary, these data suggest that bovine ELOVL6 expressed ubiquitously and is activated by SREBF1 and SP1, via two binding sites present in the ELOVL6 promoter region between -130 bp to -41bp.
PMCID: PMC5393602  PMID: 28414811
18.  Niche Regulation of Limbal Epithelial Stem Cells: Relationship between Inflammation and Regeneration 
The ocular surface  2016;14(2):100-112.
Human limbal palisades of Vogt are the ideal site for studying and practicing regenerative medicine due to their accessibility. Nonresolving inflammation in limbal stroma is common manifestation of limbal stem cell (SC) deficiency and presents as a threat to the success of transplanted limbal epithelial SCs. This pathologic process can be overcome by transplantation of cryopreserved human amniotic membrane (AM), which exerts anti-inflammatory, antiscarring and anti-angiogenic action to promote wound healing. To determine how AM might exert anti-inflammation and promote regeneration, we have purified a novel matrix, HC-HA/PTX3, responsible for the efficacy of AM efficacy. HC-HA complex is covalently formed by hyaluronan (HA) and heavy chain 1 (HC1) of inter-α-trypsin inhibitor by the catalytic action of tumor necrosis factor-stimulated gene-6 (TSG-6) and are tightly associated with pentraxin 3 (PTX3) to form HC-HA/PTX3. In vitro reconstitution of the limbal niche can be established by reunion between limbal epithelial progenitors and limbal niche cells on different substrates. In 3-dimensional Matrigel, clonal expansion indicative of SC renewal is correlated with activation of canonical Wnt signaling and suppression of canonical BMP signaling. In contrast, SC quiescence can be achieved in HC-HA/PTX3 by activation of canonical BMP signaling and non-canonical planar cell polarity (PCP) Wnt signaling, but suppression of canonical Wnt signaling. HC-HA/PTX3 is a novel matrix mitigating nonresolving inflammation and restoring SC quiescence in the niche for various applications in regenerative medicine.
PMCID: PMC4842335  PMID: 26769483
amniotic membrane; anti-inflammation; anti-angiogenesis; antiscarring; heavy chain; hyaluronan; Inter-α-inhibitor; limbus; stem cell niche; stem cells; umbilical cord
19.  G protein subunit α q regulates gastric cancer growth via the p53/p21 and MEK/ERK pathways 
Oncology Reports  2017;37(4):1998-2006.
Genetic alterations in G protein subunit α q (GNAQ) have been reported in numerous types of human cancer. However, the role of GNAQ in human gastric cancer (GC) has not been explored. In the present study, we found that GNAQ was highly expressed in GC patient samples and GNAQ expression was related to patient age, GC differentiation status and adjuvant therapy, as determined by immunohistochemical assay. Lentivirus delivery of short hairpin RNA (shRNA) targeting GNAQ was used to explore the function of GNAQ in GC cells. Silencing of GNAQ markedly suppressed proliferation and colony formation in GC cells, and arrested the cell cycle at the S phase. Mechanistic analysis revealed that knockdown of GNAQ significantly increased the expression of p53 and p21, and decreased cyclin A and p-CDK2 protein expression. Moreover, the phosphorylation of ERK and MEK was also decreased after knockdown of GNAQ as determined by western blotting assay. Overall, our results suggest that GNAQ plays a critical role in regulating GC cell growth and survival via canonical oncogenic signaling pathways including MAPK and p53, and therefore serves as a promising new therapeutic target in GC.
PMCID: PMC5367349  PMID: 28350126
GNAQ; gastric cancer; shRNA; cell proliferation; prognosis
20.  Inhibition of Proliferation and Epithelial Mesenchymal Transition in Retinal Pigment Epithelial Cells by Heavy Chain-Hyaluronan/Pentraxin 3 
Scientific Reports  2017;7:43736.
Proliferative vitreoretinopathy (PVR) is mediated by proliferation and epithelial mesenchymal transition (EMT) of retinal pigment epithelium (RPE). Because heavy chain-hyaluronic acid/pentraxin 3 (HC-HA/PTX3) purified from human amniotic membrane exerts anti-inflammatory and anti-scarring actions, we hypothesized that HC-HA/PTX3 could inhibit these PVR-related processes in vitro. In this study, we first optimized an ARPE-19 cell culture model to mimic PVR by defining cell density, growth factors, and cultivation time. Using this low cell density culture model and HA as a control, we tested effects of HC-HA/PTX3 on the cell viability (cytotoxicity), proliferation (EGF + FGF-2) and EMT (TGF-β1). Furthermore, we determined effects of HC-HA/PTX3 on cell migration (EGF + FGF-2 + TGF-β1) and collagen gel contraction (TGF-β1). We found both HA and HC-HA/PTX3 were not toxic to unstimulated RPE cells. Only HC-HA/PTX3 dose-dependently inhibited proliferation and EMT of stimulated RPE cells by down-regulating Wnt (β-catenin, LEF1) and TGF-β (Smad2/3, collagen type I, α-SMA) signaling, respectively. Additionally, HA and HC-HA/PTX3 inhibited migration but only HC-HA/PTX3 inhibited collagen gel contraction. These results suggest HC-HA/PTX3 is a non-toxic, potent inhibitor of proliferation and EMT of RPE in vitro, and HC-HA/PTX3’s ability to inhibit PVR formation warrants evaluation in an animal model.
PMCID: PMC5333089  PMID: 28252047
21.  Hepatotoxicity associated with the dietary supplement OxyELITE Pro™ — Hawaii, 2013 
Drug testing and analysis  2015;8(3-4):319-327.
Dietary supplements are increasingly marketed to and consumed by the American public for a variety of purported health benefits. On 9 September 2013, the Hawaii Department of Health (HDOH) was notified of a cluster of acute hepatitis and fulminant hepatic failure among individuals with exposure to the dietary supplement OxyELITE Pro™ (OEP). HDOH conducted an outbreak investigation in collaboration with federal partners. Physicians were asked to report cases, defined as individuals with acute onset hepatitis of unknown etiology on or after 1 April 2013, a history of weight-loss/muscle-building dietary supplement use during the 60 days before illness onset, and residence in Hawaii during the period of exposure. Reported cases’ medical records were reviewed, questionnaires were administered, and a product investigation, including chemical analyses and trace back, was conducted. Of 76 reports, 44 (58%) met case definition; of these, 36 (82%) reported OEP exposure during the two months before illness. No other common supplements or exposures were observed. Within the OEP-exposed subset, two patients required liver transplantation, and a third patient died. Excessive product dosing was not reported. No unique lot numbers were identified; there were multiple mainland distribution points, and lot numbers common to cases in Hawaii were also identified in continental states. Product analysis found consumed products were consistent with labeled ingredients; the mechanism of hepatotoxicity was not identified. We report one of the largest statewide outbreaks of dietary supplement-associated hepatotoxicity. The implicated product was OEP. The increasing popularity of dietary supplements raises the potential for additional clusters of dietary supplement-related adverse events.
PMCID: PMC4833726  PMID: 26538199
toxic hepatitis; dietary supplements
22.  Neck circumference might predict gestational diabetes mellitus in Han Chinese women: A nested case–control study 
A large neck circumference might be an indicator of metabolic syndrome and its components, and for certain patients is more practical as an index than waist circumference. The demarcation value for neck circumference that suggests metabolic syndrome appears to vary by ethnic group. Gestational diabetes mellitus is considered a component of metabolic syndrome in pregnant women. We investigated whether neck circumference in Han Chinese women is associated with gestational diabetes mellitus in early pregnancy, and determined a predictive demarcation value.
Materials and Methods
A nested case–control study was carried out with 255 women aged 18–35 years. Gestational diabetes mellitus was diagnosed according to the criteria of the American Diabetes Association through a 2‐h, 75‐g oral glucose tolerance test.
Of the total population, 41 (16%) women developed gestational diabetes mellitus by 24–28 weeks of gestation. Neck circumference at gestational week 16 positively correlated with pre‐pregnancy waist circumference, bodyweight and body mass index, and maternal age (P = 0.029) and hemoglobin A1c at gestational week 24 (P ≤ 0.001). By binary logistic regression, neck circumference was an independent predictor of gestational diabetes mellitus (odds ratio 1.840, 95% confidence interval 1.040–3.254; P = 0.036). According to the receiver operating characteristic curve, for predicting gestational diabetes mellitus the optimal demarcation for neck circumference at gestational week 16 was 35.15 cm.
Neck circumference is a viable tool to screen for gestational diabetes mellitus. In this population of pregnant Han Chinese women, a neck circumference of ≥35.15 cm was a predictor of gestational diabetes mellitus.
PMCID: PMC5334293  PMID: 27589681
Gestational diabetes mellitus; Metabolic syndrome; Neck circumference
23.  Dual inhibition of PCDH9 expression by miR-215-5p up-regulation in gliomas 
Oncotarget  2016;8(6):10287-10297.
The clinical prognosis of malignant gliomas is poor and PCDH9 down-regulation is strongly associated with its poor prognosis. But the mechanism of PCDH9 down-regulation is unknown. Abnormal miRNAs profiles regulate tumor phenotypes through inhibiting their target genes and miRNAs could inhibit target genes more efficiently by binding to both the promoter and 3′UTR of target genes. In this study, to search the dual inhibitory miRNAs which suppress PCDH9 expression in gliomas, we performed an integrative analysis of databases including miRDB, TargetScan, microPIR and miRCancer. We identified three candidate miRNAs which were predicted to bind both the promoter and 3′UTR of PCDH9 and up-regulated in gliomas. Then, we validated miR-215-5p up-regulation and PCDH9 down-regulation in glioma samples and demonstrated that miR-215-5p could inhibit the mRNA and protein levels of PCDH9 in glioma cell lines by targeting its promoter and 3′ UTR at the same time. Moreover, miR-215-5p could increase glioma cell proliferation, clone formation, in-vitro migration and reduce apoptosis via inhibiting PCDH9 expression. Our study provides evidence for a novel dual inhibition of PCDH9 by miR-215-5p in gliomas and suggests that miR-215-5p might be a therapeutic target for the treatment of gliomas.
PMCID: PMC5354659  PMID: 28055966
PCDH9; miR-215-5p; glioma; miRNA; integrative analysis
24.  Heavy Chain-Hyaluronan/Pentraxin 3 from Amniotic Membrane Suppresses Inflammation and Scarring in Murine Lacrimal Gland and Conjunctiva of Chronic Graft-versus-Host Disease 
Scientific Reports  2017;7:42195.
Chronic graft-versus-host disease (cGVHD) is a major complication of hematopoietic stem cell transplantation. Dry eye disease is the prominent ocular sequel of cGVHD and is caused by excessive inflammation and fibrosis in the lacrimal glands. Heavy chain-Hyaluronan/Pentraxin 3 (HC-HA/PTX3) is a complex purified from human amniotic membrane (AM) and known to exert anti-inflammatory and anti-scarring actions. In this study, we utilized a mouse model of cGVHD to examine whether HC-HA/PTX3 could attenuate dry eye disease elicited by cGVHD. Our results indicated that subconjunctival and subcutaneous injection of HC-HA/PTX3 preserved tear secretion and conjunctival goblet cell density and mitigated inflammation and scarring of the conjunctiva. Such therapeutic benefits were associated with suppression of scarring and infiltration of inflammatory/immune cells in the lacrimal glands. Furthermore, HC-HA/PTX3 significantly reduced the extent of infiltration of CD45+ CD4+ IL-17+ cells, CD45+ CD34+ collagen I+ CXCR4+ fibrocytes, and HSP47+ activated fibroblasts that were accompanied by upregulation of collagen type Iα1, collagen type IIIα1 and NF-kB in lacrimal glands. Collectively, these pre-clinical data help prove the concept that subcutaneous and subconjunctival injection of HC-HA/PTX3 is a novel approach to prevent dry eye disease caused by cGVHD and allow us to test its safety and efficacy in future human clinical trials.
PMCID: PMC5292704  PMID: 28165063
25.  Knockdown of COPS3 Inhibits Lung Cancer Tumor Growth in Nude Mice by Blocking Cell Cycle Progression 
Journal of Cancer  2017;8(7):1129-1136.
COPS3 encodes the third subunit of the COP9 signalosome and its aberrant expression is associated with many RITE (“Region of Increased Tumor Expression”) genes in lung cancer tissues. To elucidate the specific role of COPS3 in lung cancer, we examined its expression in lung cancer tissues by immunohistochemical staining. We found that COPS3 was overexpressed in most of the lung cancer samples examined, particularly in small cell carcinoma and squamous cell carcinoma. The expression of COPS3 protein was positively correlated with the level of Ki-67 cell proliferation index (p=0.001) and negatively related to the degree of tumor differentiation (p=0.012). In a xenograft tumor model in nude mice, shRNA-knockdown of COPS3 significantly reduced tumor growth. In lung adenocarcinoma A549 cells, shRNA-knockdown of COPS3 induced cell cycle arrest at G0/G1 phase by upregulating the cell cycle regulator protein P21 and downregulating cyclin B1 and CDK4. These data suggest that COPS3 may promote tumor growth by regulating cell-cycle associated proteins.
PMCID: PMC5463426
Lung cancer; COPS3; gene expression; xenograft tumor; cell cycle.

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