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1.  Co-grafting of neural stem cells with olfactory en sheathing cells promotes neuronal restoration in traumatic brain injury with an anti-inflammatory mechanism 
Background
We sought to investigate the effects of co-grafting neural stem cells (NSCs) with olfactory ensheathing cells (OECs) on neurological behavior in rats subjected to traumatic brain injury (TBI) and explore underlying molecular mechanisms.
Methods
TBI was established by percussion device made through a weight drop (50 g) from a 30 cm height. Cultured NSCs and OECs isolated from rats were labeled by Hoechst 33342 (blue) and chloromethyl-benzamidodialkyl carbocyanine (CM-Dil) (red), respectively. Then, NSCs and/or OECs, separately or combined, were transplanted into the area surrounding the injury site. Fourteen days after transplantation, neurological severity score (NSS) were recorded. The brain tissue was harvested and processed for immunocytochemistry, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and reverse transcription-polymerase chain reaction (RT-PCR).
Results
Significant neurological function improvement was observed in the three transplant groups, compared to the TBI group, and co-transplantation gave rise to the best improvement. Morphological evaluation showed that the number of neurons in cortex from combination implantation was more than for other groups (P <0.05); conversely, the number of apoptotic cells showed a significant decrease by TUNEL staining. Transplanted NSCs and OECs could survive and migrate in the brain, and the number of neurons differentiating from NSCs in the co-transplantation group was significantly greater than in the NSCs group. At the molecular level, the expressions of IL-6 and BAD in the co-graft group were found to be down regulated significantly, when compared to either the NSC or OEC alone groups.
Conclusion
The present study demonstrates for the first time the optimal effects of co-grafting NSCs and OECs as a new strategy for the treatment of TBI via an anti-inflammation mechanism.
doi:10.1186/1742-2094-11-66
PMCID: PMC3977666  PMID: 24690089
Neural stem cells (NSCs); Olfactory en sheathing cells (OECs); Traumatic brain injury (TBI); Anti-inflammation
2.  OECs transplantation results in neuropathic pain associated with BDNF regulating ERK activity in rats following cord hemisection 
BMC Neuroscience  2013;14:80.
Background
The olfactory ensheathing cells (OECs) derived from olfactory bulb (OB) may improve motor function after transplantation in injured spinal cord. However, the effects of OEC transplantation on sensory function have not been reported yet. The purpose of this study is to investigate whether OEC transplantation could affect the sensory function and to analyze the underlying mechanism.
Results
OEC transplantation into the hemisected spinal cords can result in hyperalgesia, indicated by radiant and mechanical stimuli towards the plantar surface in rats. This could be associated with upregulation of Brain Derived Neurotrophic Factor (BDNF), indicated by RT-PCR. Immunofluorecent staining showed that BDNF was mainly located in the neurons of the laminas I and II of the dorsal horn. Moreover, a notable upregulation on the level of p-ERK (phosphorylation of extracellular signal-regulated kinase), the downstream molecule of BDNF, was detected by using Western Blot. These findings indicate that the increased BDNF level associated with the p-ERK was possibly involved in neuropathic pain in hemisected spinal cord subjected to OEC transplantation.
Conclusions
The transplantation of OECs may induce the noticeable pain hypersensitivity in rats after hemisected spinal cord injury, and the possible mechanism may be associated with the phosphorylation of ERK and the activated BDNF overexpression.
doi:10.1186/1471-2202-14-80
PMCID: PMC3734147  PMID: 23914898
Olfactory ensheathing cells; Spinal cord injury; Hemisection; Cell transplantation; Rat; p-ERK; BDNF; Hyperalgesia
3.  Nicotinamide Phosphoribosyltransferase Inhibitor Is a Novel Therapeutic Candidate in Murine Models of Inflammatory Lung Injury 
We previously identified the intracellular nicotinamide phosphoribosyltransferase (iNAMPT, aka pre–B-cell colony enhancing factor) as a candidate gene promoting acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI) with circulating nicotinamide phosphoribosyltransferase potently inducing NF-κB signaling in lung endothelium. iNAMPT also synthesizes intracellular nicotinamide adenine dinucleotide (iNAD) in response to extracellular oxidative stress, contributing to the inhibition of apoptosis via ill-defined mechanisms. We now further define the role of iNAMPT activity in the pathogenesis of ARDS/VILI using the selective iNAMPT inhibitor FK-866. C57/B6 mice were exposed to VILI (40 ml/kg, 4 h) or LPS (1.5 mg/kg, 18 h) after osmotic pump delivery of FK-866 (100 mg/kg/d, intraperitoneally). Assessment of total bronchoalveolar lavage (BAL) protein, polymorphonuclear neutrophil (PMN) levels, cytokine levels (TNF-α, IL-6, IL-1α), lung iNAD levels, and injury scores revealed that FK-866–mediated iNAMPT inhibition successfully reduced lung tissue iNAD levels, BAL injury indices, inflammatory cell infiltration, and lung injury scores in LPS- and VILI-exposed mice. FK-866 further increased lung PMN apoptosis, as reflected by caspase-3 activation in BAL PMNs. These findings support iNAMPT inhibition via FK-866 as a novel therapeutic agent for ARDS via enhanced apoptosis in inflammatory PMNs.
doi:10.1165/rcmb.2012-0519OC
PMCID: PMC4148034  PMID: 24588101
apoptosis; FK-866; nicotinamide phosphoribosyltransferase; polymorphonuclear neutrophil; vascular endothelium
4.  methylC Track: visual integration of single-base resolution DNA methylation data on the WashU EpiGenome Browser 
Bioinformatics  2014;30(15):2206-2207.
Summary: We present methylC track, an efficient mechanism for visualizing single-base resolution DNA methylation data on a genome browser. The methylC track dynamically integrates the level of methylation, the position and context of the methylated cytosine (i.e. CG, CHG and CHH), strand and confidence level (e.g. read coverage depth in the case of whole-genome bisulfite sequencing data). Investigators can access and integrate these information visually at specific locus or at the genome-wide level on the WashU EpiGenome Browser in the context of other rich epigenomic datasets.
Availability and implementation: The methylC track is part of the WashU EpiGenome Browser, which is open source and freely available at http://epigenomegateway.wustl.edu/browser/. The most up-to-date instructions and tools for preparing methylC track are available at http://epigenomegateway.wustl.edu/+/cmtk.
Contact: twang@genetics.wustl.edu
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btu191
PMCID: PMC4103599  PMID: 24728854
5.  FGF21 protects against ox-LDL induced apoptosis through suppressing CHOP expression in THP1 macrophage derived foam cells 
Background
FGF21,as a member of the fibroblast growth factor superfamily, is an important endogenous regulator to systemic glucose and lipid metabolism. Elevated serum FGF21 levels have been reported in subjects with coronary heart disease and carotid artery plaques. The formation and apoptosis of foam cell, induced by ox-LDL and oxysterols, are key steps in the development of atherosclerosis.
Methods
In this study, THP1 derived macrophages were induced into foam cells by ox-LDL or sterols. The formation and apoptosis of foam cells treated with or without FGF21 were analyzed.
Results
We demonstrated that the accumulation of cholesterol was decreased after FGF21 treatment in THP1 macrophage derived foam cells. Consistently, the apoptosis of macrophage was alleviated dramatically with FGF21 treatment. ERK1/2 knockdown didn’t abrogate the effect of FGF21 on THP1 macrophage derived foam cells. However, FGF21 suppressed the induced expression of CHOP and DR5 in THP1 macrophage derived foam cells.
Conclusion
FGF21 protects against the formation and apoptosis of THP1 macrophages derived foam cells through suppressing the expression of CHOP.
doi:10.1186/s12872-015-0077-2
PMCID: PMC4518604
Macrophage; ER stress; FGF21; Foam cell; CHOP
6.  Polymorphisms in interleukin 17A gene and coal workers’ pneumoconiosis risk in a Chinese population 
Background
The interleukin 17A (IL-17A) which is located on chromosome 6p and has been linked to chronic inflammation, is an important candidate gene conferring coal workers’ pneumoconiosis (CWP). The purpose of this study was to investigate the genetic association between single nucleotide polymorphisms (SNPs) of IL-17A and CWP in a Chinese population.
Methods
We conducted a case–control study to investigate the role of four common SNPs in the IL-17A gene, and evaluated the relationship between these four SNPs and dust-exposure year, tobacco smoking and stages of CWP. A total of 1391 subjects was enrolled in this study, including 694 subjects in control group and 697 in case group. TaqMan based qRT-PCRs were taken to genotype rs2275913, rs3748067, rs4711998, and rs8193036 within the IL-17A gene. Luciferase assays were used to determine the effects of rs8193036 C > T alleles on the expression of IL-17A.
Results
Unconditional logistic regression analysis showed that the genotypes of rs3748067 AA (adjusted OR = 0.43, 95 % CI = 0.23–0.83) and rs8193036 TT (adjusted OR = 0.59, 95 % CI = 0.40–0.86) were associated with a decreased risk of CWP, particularly among subgroups of smokers (adjusted OR =0.34, 95 % CI = 0.13–0.86 for rs3748076; adjusted OR = 0.41, 95 % CI = 0.23–0.71 for 8193036) and CWP cases with stage I (adjusted OR = 0.45, 95 % CI = 0.21–0.98 for rs3748076; adjusted OR = 0.46, 95 % CI = 0.28–0.74 for 8193036). Furthermore, the polymorphism of rs3748067 significantly reduced the CWP risk among cases with over 27 years of dust exposure (adjusted OR = 0.42, 95 % CI = 0.18–0.97). The luciferase assays in two cell lines showed that the rs8193036 C > T substitution could reduce the expression of IL-17A, which was consistent with the findings of our association study.
Conclusions
The rs3748067 G > A and rs8193036 C > T polymorphisms decrease CWP risk. These findings could be helpful in identifying individuals at decreased risk for CWP and further studies are warranted to validate them.
doi:10.1186/s12890-015-0076-1
PMCID: PMC4520194
Genetics; IL-17A; Polymorphisms; Coal workers’ pneumoconiosis
7.  Givinostat inhibition of hepatic stellate cell proliferation and protein acetylation 
AIM: To explore the effect of the histone deacetylase inhibitor givinostat on proteins related to regulation of hepatic stellate cell proliferation.
METHODS: The cell counting kit-8 assay and flow cytometry were used to observe changes in proliferation, apoptosis, and cell cycle in hepatic stellate cells treated with givinostat. Western blot was used to observe expression changes in p21, p57, CDK4, CDK6, cyclinD1, caspase-3, and caspase-9 in hepatic stellate cells exposed to givinostat. The scratch assay was used to analyze the effect of givinostat on cell migration. Effects of givinostat on the reactive oxygen species profile, mitochondrial membrane potential, and mitochondrial permeability transition pore opening in JS-1 cells were observed by laser confocal microscopy.
RESULTS: Givinostat significantly inhibited JS-1 cell proliferation and promoted cell apoptosis, leading to cell cycle arrest in G0/G1 phases. Treatment with givinostat downregulated protein expression of CDK4, CDK6, and cyclin D1, whereas expression of p21 and p57 was significantly increased. The givinostat-induced apoptosis of hepatic stellate cells was mainly mediated through p38 and extracellular signal-regulated kinase 1/2. Givinostat treatment increased intracellular reactive oxygen species production, decreased mitochondrial membrane potential, and promoted mitochondrial permeability transition pore opening. Acetylation of superoxide dismutase (acetyl K68) and nuclear factor-κB p65 (acetyl K310) was upregulated, while there was no change in protein expression. Moreover, the notable beneficial effect of givinostat on liver fibrosis was also confirmed in the mouse models.
CONCLUSION: Givinostat has antifibrotic activities via regulating the acetylation of nuclear factor-κB and superoxide dismutase 2, thus inhibiting hepatic stellate cell proliferation and inducing apoptosis.
doi:10.3748/wjg.v21.i27.8326
PMCID: PMC4507102  PMID: 26217084
Givinostat; Hepatic stellate cells; Histone deacetylase inhibitor; Nuclear factor-κB; Superoxide dismutase
8.  REDUCED INTENSITY IN GAIT-SLIP TRAINING CAN STILL IMPROVE STABILITY 
Journal of biomechanics  2014;47(10):2330-2338.
Perturbation training with “free” slips (i.e., with long slip distance) has been able to successfully improve stability and to reduce the incidence of falls among older adults. Yet, it is unclear whether a highly constrained training with reduced slip distance (and hence training intensity) can achieve similar effects. The purpose of this study was to investigate whether short-distance slips could also improve the control of stability, and whether such improvements could be generalized to a novel, “free” slip. Thirty-six young subjects were randomly assigned to either one of the two training groups, which underwent seven training trials with constrained slips of either 12-cm or 18-cm in distance before encountering a novel, “free” slip (up to 150cm) in the test trial; or the control group, which only experienced the same test trial of a novel, “free” slip. The results showed that while both training groups were able to significantly improve their control of stability in training; the 18-cm group had significantly better reactive control of stability than the 12-cm group. During the “free” slip, such advantage enabled the 18-cm group to exhibit significantly less balance loss incidence than 12-cm group (58.3 vs. 83.3%) and the controls (100%). These differences could be fully accounted for when we assume that the central nervous system directly controls slip velocity or slip distance during adaptation, whereby the level of similarity between training trials and the test trial governs the degree of generalization. The findings that low intensity training may still improve stability warrant further investigations among older adults.
doi:10.1016/j.jbiomech.2014.04.021
PMCID: PMC4098761  PMID: 24835473
Falls reduction; Generalization; Adaptation; Perturbation training; Intervention
9.  Both TALENs and CRISPR/Cas9 directly target the HBB IVS2–654 (C > T) mutation in β-thalassemia-derived iPSCs 
Scientific Reports  2015;5:12065.
β-Thalassemia is one of the most common genetic blood diseases and is caused by either point mutations or deletions in the β-globin (HBB) gene. The generation of patient-specific induced pluripotent stem cells (iPSCs) and subsequent correction of the disease-causing mutations may be a potential therapeutic strategy for this disease. Due to the low efficiency of typical homologous recombination, endonucleases, including TALENs and CRISPR/Cas9, have been widely used to enhance the gene correction efficiency in patient-derived iPSCs. Here, we designed TALENs and CRISPR/Cas9 to directly target the intron2 mutation site IVS2-654 in the globin gene. We observed different frequencies of double-strand breaks (DSBs) at IVS2-654 loci using TALENs and CRISPR/Cas9, and TALENs mediated a higher homologous gene targeting efficiency compared to CRISPR/Cas9 when combined with the piggyBac transposon donor. In addition, more obvious off-target events were observed for CRISPR/Cas9 compared to TALENs. Finally, TALENs-corrected iPSC clones were selected for erythroblast differentiation using the OP9 co-culture system and detected relatively higher transcription of HBB than the uncorrected cells. This comparison of using TALENs or CRISPR/Cas9 to correct specific HBB mutations in patient-derived iPSCs will guide future applications of TALENs- or CRISPR/Cas9-based gene therapies in monogenic diseases.
doi:10.1038/srep12065
PMCID: PMC4496796  PMID: 26156589
10.  Inhibition of Calcium Influx Reduces Dysfunction and Apoptosis in Lipotoxic Pancreatic β-Cells via Regulation of Endoplasmic Reticulum Stress 
PLoS ONE  2015;10(7):e0132411.
Lipotoxicity plays an important role in pancreatic β-cell failure during the development of type 2 diabetes. Prolonged exposure of β-cells to elevated free fatty acids level could cause deterioration of β-cell function and induce cell apoptosis. Therefore, inhibition of fatty acids-induced β-cell dysfunction and apoptosis might provide benefit for the therapy of type 2 diabetes. The present study examined whether regulation of fatty acids-triggered calcium influx could protect pancreatic β-cells from lipotoxicity. Two small molecule compounds, L-type calcium channel blocker nifedipine and potassium channel activator diazoxide were used to inhibit palmitic acid-induced calcium influx. And whether the compounds could reduce palmitic acid-induced β-cell failure and the underlying mechanism were also investigated. It was found that both nifedipine and diazoxide protected MIN6 pancreatic β-cells and primary cultured murine islets from palmitic acid-induced apoptosis. Meanwhile, the impaired insulin secretion was also recovered to varying degrees by these two compounds. Our results verified that nifedipine and diazoxide could reduce palmitic acid-induced endoplasmic reticulum stress to generate protective effects on pancreatic β-cells. More importantly, it suggested that regulation of calcium influx by small molecule compounds might provide benefits for the prevention and therapy of type 2 diabetes.
doi:10.1371/journal.pone.0132411
PMCID: PMC4492560  PMID: 26147439
11.  Prevalence Characteristics of Coal Workers’ Pneumoconiosis (CWP) in a State-Owned Mine in Eastern China 
Coal Workers’ Pneumoconiosis (CWP) is the primary occupational disease in China. However, information about the definite prevalence of CWP is only partially available. The aims of our study were to assess the prevalence characteristics of CWP in a state-owned coal mine, evaluate the effects of control measures and develop further preventive strategies for CWP. The total study population included 495 cases who were diagnosed with CWP from the construction of this coal mine to the end of October 2014. Individuals’ information, including duration of dust exposure, job titles, age as first diagnosis, stages of CWP, CWP progress, complications with pulmonary tuberculosis, death and others were collected and analyzed. The results showed that 71.11% of 495 CWP cases were stage I and 90.71% were involved in tunneling or coal mining. The mean dust exposure period in CWP patients was 26.7 years, the mean latent period was 29.3 years and the mean diagnosed age was 50.3 years old. The proportion of CWP diagnosed after ending dust exposure were remarkably increased with the time passing. Among the CWP cases, 36 (7.27%) were complicated with pulmonary tuberculosis. The mortality of patients with stage III was the highest (60.71%) (p < 0.0001). Our data obviously show that more strict policies to protect coal miners are needed to be implemented in China, especially for tunneling and mining workers.
doi:10.3390/ijerph120707856
PMCID: PMC4515695  PMID: 26184259
prevalence characteristics; coal workers’ pneumoconiosis; China
12.  Effect of self-reported home smoking restriction on smoking initiation among adolescents in Taiwan: a prospective cohort study 
BMJ Open  2015;5(6):e007025.
Objective
The aims of this study were to investigate the influence of home smoking restriction (HSR) and the modified effect of parental smoking on smoking initiation among adolescents.
Design
Prospective Cohort Study.
Setting
Junior high school in Keelung City, Taiwan.
Participants
This study collected and evaluated primary data from the Adolescent Smoking and Other Health-Related Behaviour Survey conducted in Keelung City, which aimed to investigate smoking and health-related behaviours in junior high school students (2008–2009). Data on students free of smoking in 2008 and following them until 2009 (n=901) to ascertain whether they had started smoking were analysed with logistic regression mode to examine the proposed postulates.
Main outcome measure
The outcome variable was smoking initiation, which was defined as smoking status (yes/no) in the 2009 follow-up questionnaire. The main independent variable was HSR obtained from an adolescent self-reported questionnaire. Information on parental smoking was measured by adolescents self-reporting the smoking behaviour of their father and mother.
Results
The rate of HSR was 29.79% among 7th grade adolescents. The effect of HSR on smoking initiation in adolescents was statistically significantly modified by paternal smoking (p=0.04) but not by maternal smoking (p=0.54). The effect of HSR on smoking initiation was small for fathers with the habit of smoking (OR=0.89, 95% CI (0.42 to 1.88)), but the corresponding effect size was 3.2-fold (OR=2.84, 95% CI 1.19 to 6.81) for fathers without the habit of smoking.
Conclusions
Paternal smoking behaviour may play an interactive role with HSR in preventing smoking initiation among Taiwanese adolescents.
doi:10.1136/bmjopen-2014-007025
PMCID: PMC4486945  PMID: 26116613
PUBLIC HEALTH; SOCIAL MEDICINE
13.  Structure–Function Analysis of the Non-Muscle Myosin Light Chain Kinase (nmMLCK) Isoform by NMR Spectroscopy and Molecular Modeling: Influence of MYLK Variants 
PLoS ONE  2015;10(6):e0130515.
The MYLK gene encodes the multifunctional enzyme, myosin light chain kinase (MLCK), involved in isoform-specific non-muscle and smooth muscle contraction and regulation of vascular permeability during inflammation. Three MYLK SNPs (P21H, S147P, V261A) alter the N-terminal amino acid sequence of the non-muscle isoform of MLCK (nmMLCK) and are highly associated with susceptibility to acute lung injury (ALI) and asthma, especially in individuals of African descent. To understand the functional effects of SNP associations, we examined the N-terminal segments of nmMLCK by 1H-15N heteronuclear single quantum correlation (HSQC) spectroscopy, a 2-D NMR technique, and by in silico molecular modeling. Both NMR analysis and molecular modeling indicated SNP localization to loops that connect the immunoglobulin-like domains of nmMLCK, consistent with minimal structural changes evoked by these SNPs. Molecular modeling analysis identified protein-protein interaction motifs adversely affected by these MYLK SNPs including binding by the scaffold protein 14-3-3, results confirmed by immunoprecipitation and western blot studies. These structure-function studies suggest novel mechanisms for nmMLCK regulation, which may confirm MYLK as a candidate gene in inflammatory lung disease and advance knowledge of the genetic underpinning of lung-related health disparities.
doi:10.1371/journal.pone.0130515
PMCID: PMC4482139  PMID: 26111161
14.  Anticancer Activity of Saponins from Allium chinense against the B16 Melanoma and 4T1 Breast Carcinoma Cell 
The cytotoxic substance of A. chinense saponins (ACSs) was isolated using ethanol extraction and purified with the D101 macroporous adsorption resin approach. We investigated the anticancer activity of ACSs in the B16 melanoma and 4T1 breast carcinoma cell lines. Methylthioninium chloride and hematoxylin-eosin staining with Giemsa dyestuff were used when the cells were treated with ACSs. The results showed that the cells morphologies changed significantly; ACSs induced cell death in B16 and 4T1 cells based on acridine orange/ethidium bromide double fluorescence staining, with the number and degree of apoptotic tumor cells increasing as ACS concentration increased. ACSs inhibited the proliferation of B16 and 4T1 cells in a dose-dependent manner. They also inhibited cell migration and colony formation and exhibited a concentration-dependent effect. In addition, ACSs apparently inhibited the growth of melanoma in vivo. The preliminary antitumor in vivo assay revealed that early medication positively affected tumor inhibition action and effectively protected the liver and spleen of C57 BL/6 mice from injury. This study provides evidence for the cytotoxicity of ACSs and a strong foundation for further research to establish the theoretical basis for cell death and help in the design and development of new anticancer drugs.
doi:10.1155/2015/725023
PMCID: PMC4469801  PMID: 26146506
16.  Nonmuscle Myosin Light Chain Kinase Regulates Murine Asthmatic Inflammation 
Myosin light chain kinase (MLCK; gene code, MYLK) is a multifunctional enzyme involved in isoform-specific nonmuscle (nm) and smooth muscle contraction, inflammation, and vascular permeability, processes directly relevant to asthma pathobiology. In this report, we highlight the contribution of the nm isoform (nmMLCK) to asthma susceptibility and severity, supported by studies in two lines of transgenic mice with knocking out nmMLCK or selectively overexpressing nmMLCK in endothelium. These mice were sensitized to exhibit ovalbumin-mediated allergic inflammation. Genetically engineered mice with targeted nmMLCK deletion (nmMLCK−/−) exhibited significant reductions in lung inflammation and airway hyperresponsiveness. Conversely, mice with overexpressed nmMLCK in endothelium (nmMLCKec/ec) exhibited elevated susceptibility and severity in asthmatic inflammation. In addition, reduction of nmMLCK expression in pulmonary endothelium by small interfering RNA results in reduced asthmatic inflammation in wild-type mice. These pathophysiological assessments demonstrate the positive contribution of nmMLCK to asthmatic inflammation, and a clear correlation of the level of nmMLCK with the degree of experimental allergic inflammation. This study confirms MYLK as an asthma candidate gene, and verifies nmMLCK as a novel molecular target in asthmatic pathobiology.
doi:10.1165/rcmb.2013-0434OC
PMCID: PMC4068916  PMID: 24428690
asthma; endothelial permeability; nonmuscle myosin light chain kinase; transgenic mice
17.  FSH regulates fat accumulation and redistribution in aging through the Gαi/Ca2+/CREB pathway 
Aging Cell  2015;14(3):409-420.
Increased fat mass and fat redistribution are commonly observed in aging populations worldwide. Although decreased circulating levels of sex hormones, androgens and oestrogens have been observed, the exact mechanism of fat accumulation and redistribution during aging remains obscure. In this study, the receptor of follicle-stimulating hormone (FSH), a gonadotropin that increases sharply and persistently with aging in both males and females, is functionally expressed in human and mouse fat tissues and adipocytes. Follicle-stimulating hormone was found to promote lipid biosynthesis and lipid droplet formation; FSH could also alter the secretion of leptin and adiponectin, but not hyperplasia, in vitro and in vivo. The effects of FSH are mediated by FSH receptors coupled to the Gαi protein; as a result, Ca2+ influx is stimulated, cAMP-response-element-binding protein is phosphorylated, and an array of genes involved in lipid biosynthesis is activated. The present findings depict the potential of FSH receptor-mediated lipodystrophy of adipose tissues in aging. Our results also reveal the mechanism of fat accumulation and redistribution during aging of males and females.
doi:10.1111/acel.12331
PMCID: PMC4406670  PMID: 25754247
ageing; ca2+; endocrinology; mouse models; signal transduction; signalling
18.  A nonmuscle myosin light chain kinase–dependent gene signature in peripheral blood mononuclear cells is linked to human asthma severity and exacerbation status 
Pulmonary Circulation  2015;5(2):335-338.
Asthma is increasingly recognized as a heterogeneous disease influenced by complex genetic and environmental contributions. Myosin light chain kinase (MLCK; gene symbol, MYLK), especially the nonmuscle isoform nmMLCK, is a cytoskeleton protein known to be related to human asthma susceptibility and severity, findings confirmed in preclinical models of asthmatic inflammation. In this study, we define the central capacity for a nmMLCK-influenced gene signature in human peripheral blood mononuclear cells to predict human asthma severity and exacerbation status. We refined this signature from a list of nmMLCK-influenced genes identified in lung tissues of nmMLCK knockout mice exposed to inflammatory stimuli (ventilator-induced lung injury), with subsequent identification of nmMLCK-influenced genes in a list of human asthma severity–related genes expressed in blood. The enriched nmMLCK-influenced gene signature successfully predicted human asthma severity and exacerbation status in both discovery and validation human asthma cohorts. These findings validate the central role played by nmMLCK in asthma susceptibility, severity, and exacerbation and further provide novel gene signatures as effective asthma biomarkers for severity, exacerbation, and prognosis.
doi:10.1086/680357
PMCID: PMC4449245  PMID: 26064459
asthma exacerbation; asthma severity; nmMLCK; gene expression
19.  Regulatory Network Decoded from Epigenomes of Surface Ectoderm-Derived Cell Types 
Nature communications  2014;5:5442.
Developmental history shapes the epigenome and biological function of differentiated cells. Epigenomic patterns have been broadly attributed to the three embryonic germ layers. Here we investigate how developmental origin influences epigenomes. We compare key epigenomes of cell types derived from surface ectoderm (SE), including keratinocytes and breast luminal and myoepithelial cells, against neural crest-derived melanocytes and mesoderm-derived dermal fibroblasts to identify SE differentially methylated regions (SE-DMRs). DNA methylomes of neonatal keratinocytes share many more DMRs with adult breast luminal and myoepithelial cells than with melanocytes and fibroblasts from the same neonatal skin. This suggests that SE origin contributes to DNA methylation patterning, while shared skin tissue environment has limited effect on epidermal keratinocytes. Hypomethylated SE-DMRs are in proximity to genes with SE relevant functions. They are also enriched for enhancer- and promoter-associated histone modifications in SE-derived cells, and for binding motifs of transcription factors important in keratinocyte and mammary gland biology. Thus, epigenomic analysis of cell types with common developmental origin reveals an epigenetic signature that underlies a shared gene regulatory network.
doi:10.1038/ncomms6442
PMCID: PMC4385735  PMID: 25421844
20.  PKM2 phosphorylates MLC2 and regulates cytokinesis of tumor cells 
Nature communications  2014;5:5566.
Pyruvate kinase M2 (PKM2) is expressed at high levels during embryonic development and tumor progression and is important for cell growth. However, it is not known whether it directly controls cell division. Here, we found that Aurora B phosphorylates PKM2, but not PKM1, at T45; this phosphorylation is required for PKM2's localization and interaction with myosin light chain 2 (MLC2) in the contractile ring region of mitotic cells during cytokinesis. PKM2 phosphorylates MLC2 at Y118, which primes the binding of ROCK2 to MLC2 and subsequent ROCK2-dependent MLC2 S15 phosphorylation. PKM2-regulated MLC2 phosphorylation, which is greatly enhanced by EGF stimulation or EGFRvIII, K-Ras G12V, and B-Raf V600E mutant expression, plays a pivotal role in cytokinesis, cell proliferation, and brain tumor development. These findings underscore the instrumental function of PKM2 in oncogenic EGFR-, K-Ras-, and B-Raf-regulated cytokinesis and tumorigenesis.
doi:10.1038/ncomms6566
PMCID: PMC4259466  PMID: 25412762
PKM2; Aurora B; ROCK2; MLC2; EGFR; K-Ras; B-Raf; phosphorylation; cytokinesis
21.  Synergetic antibacterial activity of reduced graphene oxide and boron doped diamond anode in three dimensional electrochemical oxidation system 
Scientific Reports  2015;5:10388.
A 100% increment of antibacterial ability has been achieved due to significant synergic effects of boron-doped diamond (BDD) anode and reduced graphene oxide (rGO) coupled in a three dimensional electrochemical oxidation system. The rGO, greatly enhanced by BDD driven electric field, demonstrated strong antibacterial ability and even sustained its excellent performance during a reasonable period after complete power cut in the BDD-rGO system. Cell damage experiments and TEM observation confirmed much stronger membrane stress in the BDD-rGO system, due to the faster bacterial migration and charge transfer by the expanded electro field and current-carrying efficiency by quantum tunnel. Reciprocally the hydroxyl-radical production was eminently promoted with expanded area of electrodes and delayed recombination of the electron–hole pairs in presence of the rGO in the system. This implied a huge potential for practical disinfection with integration of the promising rGO and the advanced electrochemical oxidation systems.
doi:10.1038/srep10388
PMCID: PMC4440036  PMID: 25994309
22.  MicroRNA-218 inhibits the proliferation and metastasis of esophageal squamous cell carcinoma cells by targeting BMI1 
MicroRNAs (miRNAs or miRs) play a pivotal role in esophageal carcinogenesis either as oncogenes or as tumor suppressor genes. In the present study, we found that the expression level of miR-218 was significantly reduced in esophageal squamous cell carcinoma (ESCC) tissues and ESCC cell lines. Moreover, its expression was found to correlate with the clinicopathological stage of ESCC; miR-218 expression was lower in the stage III tissue samples than in the stage I and II tissue samples. Furthermore, the decreased expression of miR-218 was found to be associated with an enhanced ESCC cell proliferation and metastasis. Western blot analysis and luciferase reporter assay revealed that miR-218 decreased BMI1 expression by binding to the putative binding sites in its 3′-untranslated region (3′-UTR). The BMI1 mRNA expression levels were markedly increased and negatively correlated with the miR-218 expression level in the ESCC tissues. Functional analyses revealed that the restoration of miR-218 expression inhibited ESCC cell proliferation, migration and invasion and promoted apoptosis. The knockdown of BMI1 by siRNA showed the same phenocopy as the effect of miR-218 on ESCC cells, indicating that BMI1 was a major target of miR-218. In the present study, our findings confirm miR-218 as a tumor suppressor and identify BMI1 as a novel target of miR-218 in ESCC. Therefore, miR-218 may prove to be a useful biomarker for monitoring the initiation and development of ESCC, and may thus be an effective therapeutic target in ESCC.
doi:10.3892/ijmm.2015.2216
PMCID: PMC4494586  PMID: 25999024
microRNA-218; esophageal squamous cell carcinoma; BMI1; proliferation; metastasis
23.  Treatment of complex proximal humeral fracture: plate and tension band fixation versus conservative therapy 
Background: There is no consensus on the optimal treatment for patients with complex proximal humeral fractures. A meta-analysis was performed to evaluate clinical effectiveness of plate and tension band fixation compared with conservative therapy. Methods: We systematically searched electronic databases (Pubmed, Medline, Embase, Cochrane library and Google Scholar) to identify comparative studies and randomized controlled trials in which plate and tension band fixation was compared with conservative treatment of the complex proximal humeral fractures from 1995 to 2013. The quality of the studies was assessed and effective data were pooled for meta-analysis. Results: A total of 222 patients from three RCTs and three comparative studies were included in this meta-analysis (113 fractures treated with plate and tension band and 109 with conservative treatment). The primary and secondary outcomes (Constant Score, nonunion, avascular necrosis and osteoarthritis) were compared and there was no significant difference among these different treatments of this injury. Conclusions: Compared with conservative treatment, internal fixation including plate and tension band did not find better shoulder function, higher rate avascular necrosis of humeral head, lower rate nonunion, and higher rate osteoarthritis. In further, high quality and large randomized trials should be recommended to make a choice between these treatment modalities.
PMCID: PMC4509197  PMID: 26221252
Plate fixation; tension band fixation; conservative treatment; complex proximal humeral fracture; meta-analysis
24.  Extraordinary Capability for Water Treatment Achieved by a Perfluorous Conjugated Microporous Polymer 
Scientific Reports  2015;5:10155.
Oils, organic solvents, dyes, and heavy metal ions are primary pollutants in water resources. Currently, no sorbent material can effectively remove these types of pollutants simultaneously. Here we report a perfluorous conjugated microporous polymer with superhydrophobicity and a large surface area, which exhibits outstanding adsorption capacities, kinetics, and recyclability for a wide range of organic solvents, oils, dyes, and heavy metal ions. The adsorption capacities of this polymer, 1376.7 mg g−1 for Congo red, 808.2 mg g−1 for Pb(II) and 303.2 mg g−1 for As(V), are higher than the adsorption capacities of any previously described porous materials. Our theoretical calculation reveals that the superior properties of this polymer are due to fluorination and triple bonds within the polymer. A benchmark experiment indicates that this polymer can efficiently remove these pollutants simultaneously. Application of this polymer may lead to the development of next-generation reusable and portable water purification appliances.
doi:10.1038/srep10155
PMCID: PMC4431420  PMID: 25974738
25.  Hypermethylated Epidermal growth factor receptor (EGFR) promoter is associated with gastric cancer 
Scientific Reports  2015;5:10154.
Epidermal growth factor receptor (EGFR) is a member of the receptor tyrosine kinases ErbB family and it is found to be overexpressed in gastric cancer. However, the mechanism of the regulation of the EGFR expression is still unknown. We used the Sequenom EpiTYPER assay to detect the methylation status of the EGFR promoter in normal and tumour tissues of 30 patients with gastric cancer. We also carried out quantitative real time PCR (qPCR) to detect the expression level of EGFR in our 30 patients. Notably, increased methylation level at EGFR promoter was found in tumour tissues than the corresponding adjacent noncancerous. In both Region I DMR and Region II DMR detected in our study, tumor tissues were significantly hypermethylated (P = 2.7743E−10 and 2.1703E−05, respectively). Region I_⊿CpG_2 was also found to be associated with the presence of distant metastasis (P = 0.0323). Furthermore, the results showed a strongly significant association between the relative EGFR expression and the EGFR methylation changes in both Region I and Region II (P = 0.0004 and 0.0001, respectively). Our findings help to indicate the hypermethylation at EGFR promoter in gastric cancer and it could be a potential epigenetic biomarker for gastric cancer status and progression.
doi:10.1038/srep10154
PMCID: PMC4426697  PMID: 25959250

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